Methods For Purifying Trans-(-) Delta9-Tetrahydrocannabinol And Trans-(+)-Delta9-Tetrahydrocannabinol

ABSTRACT

Methods for making trans-(−)-Δ 9 -tetrahydrocannabinol and trans-(+)-Δ 9 -tetrahydrocannabinol are disclosed herein. In one embodiment, a trans-(−)-Δ 9 -tetrahydrocannabinol composition is prepared by allowing a composition comprising (±)-Δ 9 -tetrahydrocannabinol to separate on a chiral stationary phase to provide a trans-(−)-Δ 9 -tetrahydrocannabinol composition comprising at least about 99% by weight of trans-(−)-Δ 9 -tetrahydrocannabinol based on the total amount of trans-(−)-Δ 9 -tetrahydrocannabinol and trans-(+)-Δ 9 -tetrahydrocannabinol. The invention also relates to methods for treating or preventing a condition such as pain comprising administering to a patient in need thereof an effective amount of a trans-(−)-Δ 9 -tetrahydrocannabinol having a purity of at least about 98% based on the total weight of cannabinoids.

1. FIELD OF THE INVENTION

The present invention relates to methods for purifyingtrans-(−)-Δ⁹-tetrahydrocannabinol or trans-(+)-Δ⁹-tetrahydrocannabinol;compositions comprising purified forms oftrans-(−)-Δ⁹-tetrahydrocannabinol or trans-(+)-Δ⁹-tetrahydrocannabinol;and methods for treating or preventing a condition such as pain, emesis,loss of appetite or weight loss comprising administering purified formof trans-(−)-Δ⁹-tetrahydrocannabinol to a patient in need thereof.

2. BACKGROUND OF THE INVENTION

(−)-6a,10a-Trans-Δ⁹-tetrahydrocannabinol (“(−)-Δ⁹-THC”) is mainlyresponsible for the antiemetic effects associated with cannabis (S. E.Sallen et al., N. Engl. J. Med. 302:135 (1980); A. E. Chang et al.,Cancer 47:1746 (1981); and D. S. Poster et al., J. Am. Med. Asso.245:2047 (1981)). Both trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC, thetrans-(−)- and (+)-enantiomers, respectively, of (±)-Δ⁹-THC, arereported to be useful for treating pain, with trans-(−)-Δ⁹-THC reportedto be more potent than trans-(+)-Δ⁹-THC (see, e.g., G. Jones et al.,Biochem. Pharmacol. 23:439 (1974); S. H. Roth, Can. J. Physiol.Pharmacol. 56:968 (1978); B. R. Martin et al., Life Sciences 29:565(1981); M. Reichman et al., Mol. Pharmacol. 34:823 (1988); and M.Reichman et al., Mol. Pharmacol. 40:547 (1991)). trans-(−)-Δ⁹-THC isreported to be useful an antiemetic to relieve nausea and vomiting inpatients receiving cancer chemotherapy and to stimulate weight gain inpatients suffering from symptomatic HIV infection (see U.S. Pat. No.6,703,418 B2 to Plasse). An encapsulated formulation of synthetictrans-(−)-Δ⁹-THC (“dronabinol”) in sesame oil is currently sold asMarinol® by Unimed Pharmaceuticals, Inc., in 2.5, 5, and 10 mg dosagestrengths.

Trans-(−)-Δ⁹-THC can be extracted from hashish (see, Y. Gaoni et al., J.Am. Chem. Soc. 93:217 (1971); and U.S. Pat. No. 6,365,416 B1 to Elsohlyet al.). The concentration of trans-(−)-Δ⁹-THC in hashish, however,ranges from only about 1-5% depending on the source, and, even afterextraction, trans-(−)-Δ⁹-THC must be separated from other impuritiessuch as cannabinoid isomers.

R. F. Turk et al., J. Pharm. Pharmac. 23:190-195 (1971) describes amethod for isolating trans-(−)-Δ⁹-THC from marihuana, but the productcontained an undetermined amount of carboxylic precursors of THC.

The following paragraphs relate to known methods that purport makingtrans-(−)-Δ⁹-THC or (±)-Δ⁹-THC:

U.S. Pat. No. 3,560,528 to Petrizilka describes the reaction of(+)-p-mentha-2,8-dien-1-ol with olivetol in the presence ofp-toluenesulfonic acid monohydrate (“PTSA.H₂O”) or trifluoroacetic acidin refluxing benzene to provide (−)-Δ⁸-THC, which can be converted totrans-(−)-Δ⁹-THC by addition of HCl followed by dehydrochlorination (seeY. Mechoulam et al., J. Am. Chem. Soc. 89:4553 (1967); and R. Mechoulamet al., J. Am. Chem. Soc. 94:6159 (1972)).

U.S. Pat. No. 4,025,516 to Razdan et al. describes the reaction of amixture of cis/trans-(+)-p-mentha-2,8-dien-1-ol with olivetol in aninert organic solvent in the presence of an excess of a non-alkalinedehydrating agent and an acid catalyst to form trans-(−)-Δ⁹-THC; thispatent also describes the reaction of (−)-cannabidiol (“(−)-CBD”) or(−)-abnormal-CBD (“(−)-abn-CBD”) with a Lewis acid such as borontrifluoride diethylether (“BF₃.Et₂O”) in an inert solvent underanhydrous conditions to form trans-(−)-Δ⁹-THC.

R. K. Razdan et al., J. Am. Chem. Soc. 96:5860 (1974) describes thereaction of a mixture of cis/trans-(+)-p-mentha-2,8-dien-1-ol witholivetol in the presence of 1% BF₃.Et₂O, methylene chloride andanhydrous magnesium sulfate to form trans-(−)-Δ⁹-THC.

U.S. Pat. No. 4,381,399 to Olsen et al. describes a method forseparating trans-(−)-Δ⁹-THC from a crude synthetic mixture, the methodcomprising esterifying the crude mixture, isolating the resultanttrans-(−)-Δ⁹-THC ester, hydrolyzing the ester, and distillingtrans-(−)-Δ⁹-THC at reduced pressure.

K. E. Fahrenholtz et al., J. Am. Chem. Soc. 89:5934-5941 (1967)describes the hydrolysis of(±)-1-m-nitrobenzenesulfoanate-6a,10a-trans-Δ⁹-tetrahydrocannabinol withNaOH in aqueous methanol to provide (±)-Δ⁹-THC, which was subsequentlycrystallized from hexane.

E. G. Taylor et al., J. Am. Chem. Soc. 88:367 (1966) describes thereaction of citral with olivetol in acidified ethanol to form (±)-Δ⁹-THCin about 35% yield.

S. L. Levin et al., J. Chromatogr. A 654:53-64 (1993) describe a methodfor resolving trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC from a compositioncomprising equimolar amounts of the trans-(−)- and (+)-enantiomer.

Despite these described methods, there remains a need for improvedmethods for making trans-(−)-Δ⁹-THC in pure or substantially pure form.

Citation of any reference in Section 2 of this application is not anadmission that the reference is prior art to the application.

3. SUMMARY OF THE INVENTION

The invention relates to methods for preparing a composition comprisingtrans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC.

In one embodiment, the invention relates to a method for preparing acomposition comprising at least about 98% by weight of trans-(−)-Δ⁹-THCbased on the total amount of cannabinoids.

In another embodiment, the invention relates to a method for preparing acomposition comprising trans-(−)-Δ⁹-THC, comprising:

allowing a composition comprising (±)-Δ⁹-THC and an eluting solvent toseparate on a chiral stationary phase to provide a trans-(−)-Δ⁹-THCcomposition, wherein the (±)-Δ⁹-THC is obtained from crystalline(±)-Δ⁹-THC.

In another embodiment, the invention relates to a method for preparing atrans-(−)-Δ⁹-THC composition, comprising:

allowing a composition comprising (±)-Δ⁹-THC and an eluting solvent toseparate on a chiral stationary phase to provide a trans-(−)-Δ⁹-THCcomposition comprising at least about 98% by weight of trans-(−)-Δ⁹-THCbased on the total amount of trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC;

wherein the (±)-Δ⁹-THC was obtained by allowing trans-(−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC to crystallize from a first composition comprisingtrans-(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC, and a non-polar organic solvent toprovide crystalline (±)-Δ⁹-THC and a liquid phase.

The invention also relates to methods for preparing a compositioncomprising at least about 98% by weight of trans-(+)-Δ⁹-THC based on thetotal amount of cannabinoids.

In one embodiment, the invention relates to a method for preparing acomposition comprising trans-(+)-Δ⁹-THC, comprising:

allowing a composition comprising (±)-Δ⁹-THC and an eluting solvent toseparate on a chiral stationary phase to provide a trans-(+)-Δ⁹-THCcomposition, wherein the (±)-Δ⁹-THC is obtained from crystalline(±)-Δ⁹-THC.

In another embodiment, the invention relates to a method for preparing atrans-(+)-Δ⁹-THC composition, comprising:

allowing a composition comprising (±)-Δ⁹-THC and an eluting solvent toseparate on a chiral stationary phase to provide a trans-(+)-Δ⁹-THCcomposition comprising at least about 98% by weight of thetrans-(+)-Δ⁹-THC based on the total amount of the trans-(+)-Δ⁹-THC andtrans-(−)-Δ⁹-THC;

wherein the (±)-Δ⁹-THC was obtained by allowing trans-(−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC to crystallize from a first composition comprisingtrans-(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC, and a non-polar organic solvent toprovide crystalline (±)-Δ⁹-THC and a liquid phase.

The invention also relates to compositions comprising eithertrans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC.

In one embodiment, the invention relates to a composition comprising atleast 99.0% by weight of trans-(−)-Δ⁹-THC based on the total amount ofcannabinoids.

In another embodiment, the invention relates to a composition comprisingat least 99.0% by weight of trans-(+)-Δ⁹-THC based on the total amountof cannabinoids.

The invention also relates to pharmaceutical compositions comprisingtrans-(−)-Δ⁹-THC. In one embodiment, the invention relates topharmaceutical compositions comprising at least 99.0% by weight oftrans-(−)-Δ⁹-THC based on the total amount of cannabinoids.

The invention still further relates to methods for treating orpreventing a condition such as, e.g., emesis, loss of weight or loss ofappetite comprising administering to a patient in need thereof aneffective amount of a composition comprising at least 99.0% by weight oftrans-(−)-Δ⁹-THC based on the total amount of cannabinoids.

The present invention can be understood more fully by reference to thefollowing detailed description and illustrative examples, whichexemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1. Definitions

As used herein, the generic term “Δ⁹-THC” refers to trans-(−)-Δ⁹-THC,trans-(+)-Δ⁹-THC, (±)-Δ⁹-THC, or any mixture thereof.

trans-(−)-Δ⁹-THC has the structure of formula (1a):

Trans-(+)-Δ⁹-THC has the structure of (1b):

As used herein, the generic term “Δ⁸-THC” refers to (−)-Δ⁸-THC,(+)-Δ⁸-THC, (±)-Δ⁸-THC, or any mixture thereof.

(−)-Δ⁸-THC has the structure of formula (2a):

(+)-Δ⁸-THC has the structure of (2b):

As used herein, the generic term “CBD” refers to (−)-CBD, (+)-CBD,(±)-CBD, or any mixture thereof.

(−)-CBD has the structure of formula (3a):

(+)-CBD has the structure of formula (3b):

As used herein, the generic term “CBD-bis-1,3-(3,5-dinitrobenzoate)”refers to (−)-CBD-bis(3,5-dinitrobenzoate),(+)-CBD-bis(3,5-dinitrobenzoate), (±)-CBD-bis(3,5-dinitrobenzoate), orany mixture thereof.

(−)-CBD-bis(3,5-dinitrobenzoate) has the structure of formula (4a):

where R is —C(O)(3,5-C₆H₃(NO₂)₂).

(+)-CBD-bis(3,5-dinitrobenzoate) has the structure of formula (4b):

where R is —C(O)(3,5-C₆H₃(NO₂)₂).

As used herein, the generic term “trans-Δ⁹-THC carboxylic acid” refersto trans-(−)-Δ⁹-THC carboxylic acid, trans-(+)-Δ⁹-THC carboxylic acid,trans-(±)-Δ⁹-THC carboxylic acid, or any mixture thereof

trans-(−)-Δ⁹-THC carboxylic acid has the structure of formula (5a):

trans-(+)-Δ⁹-THC carboxylic acid has the structure of formula (5b):

The term “halide” refers to fluoride, chloride, bromide or iodide.

The term “-halo” means —F, —Cl, —Br or —I.

The term “—(C₁-C₄)alkyl” means a saturated straight-chain or branchedhydrocarbon having from 1 to 4 carbon atoms. Representative saturatedstraight chain (C₁-C₄)alkyls are -methyl, -ethyl, -n-propyl, and-n-butyl. Representative saturated branched —(C₁-C₄)alkyls are-isopropyl, -sec-butyl, -isobutyl, and -tert butyl.

The phrase “anhydrous organic solvent,” unless otherwise defined herein,means an organic solvent having an amount of water that is less thanabout 0.01% by weight of the total amount of water and organic solvent.

The term “cannabinoids” refers to Δ⁹-THC including trans-Δ⁹-THC andcis-Δ⁹-THC; structural isomers of Δ⁹-THC having a molecular formulaC₂₁H₃₀O₂, including Δ⁸-THC, (−)-Δ⁸-iso-THC, and (+)-Δ⁸-iso-THC;cannabinol and structural isomers of cannabinol having a molecularformula of C₂₁H₂₈O₂; Δ⁹-THC-carboxylic acid; Δ⁹-THC precursors includingCBD, abn-CBD, (+)-abn-CBD, olivetol, (+)-p-mentha-2,8-dien-1-ol and(−)-p-mentha-2,8-dien-1-ol; salts thereof; and derivatives thereofincluding acids, ethers, esters, amines, and the like.

Unless otherwise specified herein, the phrase “cannabinoid impurities”means cannabinoids other than trans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC.

Unless otherwise specified herein, the generic term “Δ⁹-THC-carboxylicacid” means (−)-Δ⁹-THC-carboxylic acid, (+)-Δ⁹-THC-carboxylic acid, or(±)-THC-carboxylic acid.

As used herein, the phrase “crystalline (±)-Δ⁹-THC” means a solid formof Δ⁹-THC comprising about equimolar amounts of trans-(−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC and having an amount of trans-(−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC that is at least about 95% by weight based on the totalweight of cannabinoids. As used herein, the term “patient” means ananimal, including, but not limited, to an animal such a cow, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guineapig, etc., and is more preferably a mammal, and most preferably a human

4.2. Methods for Purifying Trans-(−)-Δ⁹-THC

As noted above, the present invention relates methods for makingcompositions comprising at least about 98% by weight of trans-(−)-Δ⁹-THCor trans-(+)-Δ⁹-THC based on the total amount of cannabinoids.

In one embodiment, the invention relates to a method comprising allowinga composition comprising (±)-Δ⁹-THC and an eluting solvent to separateon a chiral stationary phase to provide a trans-(−)-Δ⁹-THC ortrans-(+)-Δ⁹-THC composition, wherein the (±)-Δ⁹-THC is obtained fromcrystalline (±)-Δ⁹-THC. Without being limited by theory, Applicantsbelieve that cannabinoid impurities typically present in Δ⁹-THCcompositions are substantially, if not completely, removed whentrans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC are allowed to form crystalline(±)-Δ⁹-THC. Subsequent resolution of (±)-Δ⁹-THC obtained fromcrystalline (±)-Δ⁹-THC with an eluting solvent on a chiral stationaryphase provides a composition comprising at least about 98% by weight oftrans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC based on the total amount ofcannabinoids.

In one embodiment, the invention relates to a method for preparing acomposition comprising trans-(−)-Δ⁹-THC, comprising:

allowing a composition comprising (±)-Δ⁹-THC and an eluting solvent toseparate on a chiral stationary phase to provide a trans-(−)-Δ⁹-THCcomposition, wherein the (±)-Δ⁹-THC is obtained from crystalline(±)-Δ⁹-THC.

In another embodiment, the invention relates to a method for preparing acomposition comprising trans-(+)-Δ⁹-THC, comprising:

allowing a composition comprising (±)-Δ⁹-THC and an eluting solvent toseparate on a chiral stationary phase to provide a trans-(+)-Δ⁹-THCcomposition, wherein the (±)-Δ⁹-THC is obtained from crystalline(±)-Δ⁹-THC.

Crystalline (±)-Δ⁹-THC useful in the present invention can be obtainedby any known or later-developed method. For example, a non-limitingmethod for obtaining crystalline (±)-Δ⁹-THC includes crystallizationfrom a first composition comprising trans-(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC,and a non-polar organic solvent to provide crystalline (±)-Δ⁹-THC asdescribed below in Section 4.3.

In another embodiment, the invention relates to a method for preparing atrans-(−)-Δ⁹-THC composition, comprising:

allowing a composition comprising (±)-Δ⁹-THC and an eluting solvent toseparate on a chiral stationary phase to provide a trans-(−)-Δ⁹-THCcomposition comprising at least about 98% by weight of trans-(−)-Δ⁹-THCbased on the total amount of trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC;

wherein the (±)-Δ⁹-THC was obtained by allowing trans-(−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC to crystallize from a first composition comprisingtrans-(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC, and a non-polar organic solvent toprovide crystalline (±)-Δ⁹-THC and a liquid phase.

In another embodiment, the invention relates to a method for preparing atrans-(+)-Δ⁹-THC composition, comprising:

allowing a composition comprising (±)-Δ⁹-THC and an eluting solvent toseparate on a chiral stationary phase to provide a trans-(+)-Δ⁹-THCcomposition comprising at least about 98% by weight of trans-(+)-Δ⁹-THCbased on the total amount of trans-(+)-Δ⁹-THC and trans-(−)-Δ⁹-THC;

wherein the (±)Δ⁹-THC was obtained by allowing trans-(−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC to crystallize from a first composition comprisingtrans-(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC, and a non-polar organic solvent toprovide crystalline (±)-Δ⁹-THC and a liquid phase.

Compositions comprising trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC useful forobtaining crystalline (±)-Δ⁹-THC can be obtained by methods described inSection 4.3.

4.3. The Crystallizing Step

As noted above, crystalline (±)-Δ⁹-THC can, in one embodiment, beobtained by allowing trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC tocrystallize from a composition comprising trans-(−)-Δ⁹-THC,trans-(+)-Δ⁹-THC and a non-polar organic solvent (the “CrystallizingStep”) to provide crystalline (±)-Δ⁹-THC and a liquid phase.Compositions comprising trans-(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC and anon-polar organic solvent useful for the Crystallizing Step can beobtained by any known or later-developed method.

For example, crystalline (±)-Δ⁹-THC can be obtained by contacting asuitable amount of trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC with anon-polar organic solvent. The order and rate of addition of thetrans-(−)-Δ⁹-THC, the trans-(+)-Δ⁹-THC and the non-polar organic solventis not critical and can be carried out sequentially or substantiallysimultaneously. As an example, trans-(−)-Δ⁹-THC, optionally in thepresence of a non-polar organic solvent, and trans-(+)-Δ⁹-THC,optionally in the presence of a non-polar organic solvent, can be addedto a non-polar organic solvent. Likewise, trans-(+)-Δ⁹-THC in thepresence of a non-polar organic solvent and trans-(−)-Δ⁹-THC in thepresence of a non-polar organic solvent can be admixed.

Trans-(−)-Δ⁹-THC can be obtained from natural products or by syntheticmethods. In one embodiment, trans-(−)-Δ⁹-THC is obtained from a naturalproduct such as, e.g., hashish or marijuana (see Y. Gaoni et al., J. Am.Chem. Soc. 93:217 (1971); and U.S. Pat. No. 6,365,416 B1 to Elsohly etal.).

Trans-(−)-Δ⁹-THC can also be obtained by known synthetic methodsincluding, but not limited to, reaction of cis/trans mixture of(+)-p-mentha-2,8-dien-1-ol with olivetol in the presence of an acidcatalyst such a para-toluenesulfonic acid and a dehydrating agent (seeU.S. Pat. No. 3,560,528 to Petrizilka and U.S. Pat. No. 4,025,516 toRazdan et al.); reaction of (−)-CBD with a Lewis acid such as BF₃.Et₂Oin an inert solvent under anhydrous conditions (see U.S. Pat. No.4,025,516 to Razdan et al.; and International publication no. WO03/070506); or reaction of (−)-Δ⁸-THC with HCl followed bydehydrochlorination (see Y. Mechoulam et al., J. Am. Chem. Soc. 89:4553(1967); and R. Mechoulam et al., J. Am. Chem. Soc. 94:6159 (1972)).Alternatively, trans-(−)-Δ⁹-THC can be obtained by methods described inSection 5.

Trans-(+)-Δ⁹-THC, which is not known to occur in nature, can be made byknown synthetic methods including, but not limited to, reaction of(+)-Δ⁸-THC with HCl followed by dehydrochlorination (see R. Mechoulam etal., J. Am. Chem. Soc. 94:6159 (1972). Alternatively, trans-(+)-Δ⁹-THCcan be obtained by methods described in Section 5. In one embodiment,trans-(+)-Δ⁹-THC used in the Crystallizing Step is “recycled” from aprevious resolution of (±)-Δ⁹-THC on a chiral stationary phase asdescribed in Section 4.4

In another embodiment, the trans-(−)-Δ⁹-THC and trans-(+)Δ⁹-THC used inthe Crystallizing Step can be obtained as a mixture of enantiomers by adirect synthetic method. When a synthetic method is used, the ratio oftrans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC can vary depending on the opticalpurity of the reagents and the synthetic process. In one embodiment,trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC are obtained in about equimolaramounts by a synthetic route using racemic reagents. Non-limitingmethods for preparing trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC by a directsynthetic route include reaction of citral and olivetol in the presenceof a Lewis acid (see R. Mechoulam et al., J. Am. Chem. Soc. 94:6159(1972)) or hydrolysis of(±)-1-m-nitrobenzenesulfoanate-6a,10a-trans-Δ⁹-THC with NaOH in aqueousmethanol (K. E. Fahrenholtz et al., J. Am. Chem. Soc. 89:5934-5941(1967)). Alternatively, (±)-Δ⁹-THC can be obtained by methods describedin Section 5.

In yet another embodiment, the trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THCused in the Crystallizing Step can be obtained from derivatives oftrans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC. For example, an admixture oftrans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC can be reacted with a phenolprotecting group such as m-nitrobenzenesulfonate and crystallized toprovide 2-m-nitrobenzenesulfonate-(±)-Δ⁹-THC (see U.S. Pat. No.3,507,885 to Fahrenholtz; and K. E. Fahrenholtz et al., J. Am. Chem.Soc. 89:5934-5491 (1967))). The 2-m-nitrobenzenesulfonate-(±)-Δ⁹-THC canthen be deprotected, and the resultant composition comprisingtrans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC can be crystallized from acomposition comprising the trans-(−)-Δ⁹-THC, the trans-(+)-Δ⁹-THC, and anon-polar organic solvent to provide crystalline (±)-Δ⁹-THC.

The ratio of trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC used in theCrystallizing Step can vary. In one embodiment, the trans-(−)-Δ⁹-THC ispresent in an amount from about 0.75 to about 1.25 molar equivalents permolar equivalent of trans-(+)-Δ⁹-THC. In another embodiment, thetrans-(−)-Δ⁹-THC is present in an amount from about 0.9 to about 1.1molar equivalents per molar equivalent of trans-(+)-Δ⁹-THC. In anotherembodiment, the trans-(−)-Δ⁹-THC is present in an amount from about 0.95to about 1.05 molar equivalents per molar equivalent oftrans-(+)-Δ⁹-THC. And in another embodiment, the trans-(−)-Δ⁹-THC ispresent in an amount of about 1 molar equivalent per molar equivalent oftrans-(+)-Δ⁹-THC.

Non-limiting examples of non-polar organic solvents that are useful inthe Crystallizing Step include aliphatic (C₄-C₁₀)hydrocarbons such asbutane, pentane, hexane, heptane, octane, nonane, decane, includingstraight-chained aliphatic hydrocarbons, branched aliphatic hydrocarbonsand cyclic aliphatic hydrocarbons, or any mixture thereof.

In one embodiment, the non-polar organic solvent used in theCrystallizing Step is a straight-chain or branch-chain heptane. Inanother embodiment, the non-polar organic solvent used in theCrystallizing Step is pentane, hexane, heptane, octane or isooctane. Inanother embodiment, the non-polar organic solvent used in theCrystallizing Step is n-heptane.

The amount of the non-polar organic solvent used in the CrystallizingStep can vary and will depend, in part, on the amount and type ofcannabinoid impurities and temperature. Typically, the non-polar organicsolvent is present in an amount sufficient to provide a mixture having aΔ⁹-THC concentration from about 1% to about 95%, preferably from about20% to about 75%, more preferably from about 40% to about 60% by weightbased on the total amount of Δ⁹-THC and the non-polar organic solvent.

The Crystallizing Step is carried out for a time and at a temperaturesufficient to provide (±)-Δ⁹-THC crystals. A time sufficient tocrystallize (±)-Δ⁹-THC is from about 1 hour to about 200 hours; inanother embodiment, from about 5 hours to about 150 hours; in anotherembodiment, from about 25 hours to about 100 hours; and in anotherembodiment, from about 30 hours to about 75 hours.

Typically, a temperature sufficient to provide crystalline (±)-Δ⁹-THC isfrom about −78° C. to about 100° C.; in another embodiment, from about−50° C. to about 25° C.; in another embodiment, from about −30° C. toabout 0° C.; and in another embodiment, from about −25° C. to about −15°C.

In certain embodiments, the Crystallizing Step is carried out at two ormore temperatures. In one embodiment, the composition comprisingtrans-(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC and a non-polar organic solvent isprepared at a first temperature, e.g., 20° C. or higher. Without beinglimited by theory, Applicants believe that forming the composition at atemperature of 20° C. or higher increases the solubility of thetrans-(−)-Δ⁹-THC and the trans-(+)-Δ⁹-THC in the non-polar organicsolvent. The temperature of the admixture can then be decreased to asecond temperature, e.g., 0° C. or lower. Without being limited bytheory, Applicants believe that holding the admixture at a temperatureof 0° C. or lower decreases the solubility of (±)-Δ⁹-THC and promotescrystallization. Optionally, the temperature of the admixture can befurther decreased to third temperature, e.g., −20 to −15° C. As notedabove, such a decrease in temperature is believed to enhance the(±)-Δ⁹-THC crystallization process.

In one embodiment, trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC are dissolvedin a non-polar organic solvent; the resultant solution is cooled toabout 0° C.; the resultant mixture is further cooled to about −15° C.;and the resultant crystalline (±)-Δ⁹-THC is separated from the liquidphase.

In another embodiment, the Crystallizing Step is carried out in thepresence of a seed crystal. Typically, the seed crystal, when used, isadded to the cold (e.g., 0° C. or lower) admixture comprisingtrans-(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC and the non-polar organic solvent. Inone embodiment, the seed crystal is (±)-Δ⁹-THC.

The progress of the Crystallizing Step can be monitored visually orusing conventional analytical techniques, including, but not limited to,thin-layer chromatography (“TLC”), high-performance liquidchromatography (“HPLC”), gas chromatography (“GC”), gas-liquidchromatography (“GLC”), infrared spectroscopy (“IR”), Raman spectroscopy(“Raman”) and nuclear magnetic resonance spectroscopy (“NMR”) such as ¹Hor ¹³C NMR.

The Crystallizing Step can be carried out at reduced pressure,atmospheric pressure or elevated pressure. In one embodiment, theCrystallizing Step is carried out at atmospheric pressure.

In one embodiment, certain impurities are removed from thetrans-(−)-Δ⁹-THC and/or trans-(+)-Δ⁹-THC compositions prior to carryingout the Crystallizing Step. Non-limiting methods for removing impuritiesprior to carrying out the Crystallizing Step include columnchromatography (see Section 4.4) or extraction under basic conditions asdescribed below.

In one embodiment, (+)-Δ⁹-THC, (−)-Δ⁹-THC, or (±)-Δ⁹-THC is contactedwith base prior to carrying out the Crystallizing Step.

In another embodiment, the invention also relates to a method forpurifying trans-(+)-Δ⁹-THC, trans-(−)-Δ⁹-THC, or trans-(±)-Δ⁹-THC (the“Δ⁹-THC Purification Method”) comprising:

contacting trans-(+)-Δ⁹-THC, trans-(−)-Δ⁹-THC, or trans-(±)-Δ⁹-THC witha first water-immiscible organic solvent, a water-miscible alcohol,water, and an alkali metal hydroxide (the “Caustic Contacting Step”) toform a biphasic mixture comprising (i) a first organic phase and (ii) analcoholic-caustic phase comprising trans-(−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC.

Without being limited by theory, it is believed that the CausticContacting Step extracts impurities from the Δ⁹-THC-containingalcoholic-caustic phase into the first organic phase, which impuritiesmay impede or prevent (±)-Δ⁹-THC from crystallizing from the compositioncomprising the trans-(−)-Δ⁹-THC, the trans-(+)-Δ⁹-THC, and the non-polarorganic solvent.

The amount of alkali metal hydroxide used in the Caustic Contacting Steptypically ranges from about 1 to about 1000 molar equivalents per molarequivalent of Δ⁹-THC; in another embodiment, the amount of alkali metalhydroxide ranges from about 10 to about 100 molar equivalents per molarequivalent of trans-Δ⁹-THC; and in another embodiment, amount of alkalimetal hydroxide ranges from about 25 to about 55 molar equivalents permolar equivalent of trans-Δ⁹-THC.

Non-limiting examples of water-miscible alcohols useful in the CausticContacting Step include methanol, ethanol, isopropanol, or anycombination thereof. In one embodiment, the water-miscible alcohol ismethanol.

The amount of water-miscible alcohol used in the Caustic Contacting Steptypically is from about 1 part to about 100 parts by weight based on theweight of the alkali metal hydroxide; in another embodiment, the amountof water-miscible alcohol is from about 1 part to about 25 parts byweight based on the weight of the alkali metal hydroxide; and in anotherembodiment, the amount of water-miscible alcohol is from about 5 partsto about 10 parts by weight based on the weight of the alkali metalhydroxide.

Non-limiting examples of first water-immiscible organic solvents usefulin the Caustic Contacting Step include the non-polar organic solventsdescribed above for the Crystallizing Step. In one embodiment, the firstwater-immiscible solvent is heptane.

The amount of first water-immiscible organic solvent used in the CausticContacting Step typically is from about 1 part to about 1000 parts byweight based on the weight of the Δ⁹-THC; in another embodiment, theamount of water-immiscible organic solvent is from about 5 parts toabout 100 parts by weight based on the weight of the Δ⁹-THC; and inanother embodiment, the amount of water-immiscible organic solvent isfrom about 5 parts to about 20 parts by weight based on the weight ofthe Δ⁹-THC.

The Caustic Contacting Step can be carried out by methods known in theart such as, but not limited to, stirring, shaking, countercurrentcascade, and ultrasound. admixing, pumping. The Caustic Contacting Stepcan also be carried out by methods useful for liquid-liquid extraction(see, e.g., Lo et al., Extraction, in 7 Kirk-Othmer Encyc. of Chem.Technol. 349-381 (4th ed. 1993), the entire contents of which areincorporated herein by reference).

The Caustic Contacting Step typically is carried out from about 0.25hours to about 50 hours; in another embodiment, from about 0.25 hours toabout 10 hours; and in another embodiment, from about 0.25 hours toabout 2 hours.

The Caustic Contacting Step is typically carried at a temperature offrom about 0° C. to about 100° C.; in another embodiment, from about 20°C. to about 50° C.; and in another embodiment, from about 20° C. toabout 30° C.

The Caustic Contacting Step can be carried out at reduced pressure,atmospheric pressure (i.e., about 1 atmosphere), or elevated pressure.In one embodiment, the Caustic Contacting Step is carried out atatmospheric pressure.

The progress of the Caustic Contacting Step can be monitored usingconventional techniques as described above for the Crystallizing Step.

In another embodiment, the trans-Δ⁹-THC Purification Method of thepresent invention further comprises contacting the alcoholic-causticphase with an acid to provide an acid-treated alcoholic phase. Withoutbeing limited by theory, it is believed that trans-Δ⁹-THC is immisciblein the acidified alcoholic phase. Non-limiting examples of useful acidsinclude citric acid, acetic acid, and the like. In one embodiment, theacid is citric acid.

Typically, the acid, is added in an amount sufficient to achieve a pH offrom about 5 to about 9. In another embodiment, the acid is added in anamount sufficient to achieve a pH from about 6 to about 8; in anotherembodiment, the acid is added in an amount sufficient to achieve a pH offrom about 7 to about 8.

In another embodiment, the Δ⁹-THC Purification Method of the presentinvention further comprises contacting the acid-treated alcoholic phasewith a second water-immiscible organic solvent to form (i) a secondorganic phase comprising trans-(−)Δ⁹-THC and (ii) an acid-treatedalcoholic phase.

Non-limiting examples of second water-immiscible organic solvents usefulfor contacting the acid-treated alcoholic phase to form a second organicphase comprising trans-Δ⁹-THC include the non-polar organic solventsdescribed above for the Crystallizing Step. In one embodiment, thesecond water-immiscible organic solvent is heptane. The amount of firstwater-immiscible organic solvent used is typically is from about 1 partto about 1000 parts by weight based on the weight of the trans-Δ⁹-THC;in another embodiment, the amount of water-immiscible organic solvent isfrom about 1 part to about 50 parts by weight based on the weight of thetrans-Δ⁹-THC; and in another embodiment, the amount of water-immiscibleorganic solvent is from about 1 part to about 10 parts by weight basedon the weight of the trans-Δ⁹-THC. Methods useful for contacting theacid-treated alcoholic phase with a second water-immiscible organicsolvent include those described above for the Caustic Contacting Step.

In another embodiment, the Δ⁹-THC Purification Method of the presentinvention further comprises separating the second organic phase from theacid-treated alcoholic phase. Methods useful for separating the secondorganic phase from the acid-treated alcoholic phase include thosedescribed above for separating the first organic phase from thealcoholic-caustic phase. After separation from the acid-treatedalcoholic phase, the second organic phase is typically dried by, e.g.,azeotropic distillation and/or contacting the second organic phase witha drying agent (e.g., Na₂SO₄ or MgSO₄).

In another embodiment, the Δ⁹-THC Purification Method of the presentinvention further comprises concentrating the second organic phase toform a concentrated second organic phase comprising trans-Δ⁹-THC. Anon-limiting method useful for concentrating the second organic phase isdistillation. When the second organic phase is concentrated bydistillation, the distillation can be carried out at elevated pressure,atmospheric pressure, or at reduced pressure. In one embodiment, thedistillation is carried out at atmospheric pressure. In anotherembodiment, the distillation is carried out at reduced pressure.

In another embodiment, the Δ⁹-THC Purification Method of the presentinvention further comprises contacting the concentrated second organicphase with a non-polar organic solvent to form a first organiccomposition comprising trans-Δ⁹-THC. The amount and type of non-polarorganic solvent are those described above in the Crystallizing Step forthe non-polar organic solvent.

In another embodiment, the trans-Δ⁹-THC used in the Δ⁹-THC PurificationMethod comprises trans-(−)-Δ⁹-THC. In another embodiment, thetrans-Δ⁹-THC used in the Δ⁹-THC Purification Method comprisestrans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC. In another embodiment, thetrans-Δ⁹-THC used in the Δ⁹-THC Purification Method comprisestrans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC, wherein the trans-(−)-Δ⁹-THC ispresent in an amount from about 0.75 to about 1.25 molar equivalents permolar equivalent of trans-(+)-Δ⁹-THC.

In another embodiment, the Δ⁹-THC Purification Method of the presentinvention further comprises:

adding trans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC to the first organiccomposition in an amount sufficient to provide a second organiccomposition comprising (−)-Δ⁹-THC and trans-(+)-Δ⁹-THC, wherein thetrans-(−)-Δ⁹-THC is present in an amount from about 0.75 to about 1.25molar equivalents per molar equivalent of trans-(+)-Δ⁹-THC; and

allowing trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC to crystallize from thefirst organic composition to provide crystalline (±)-Δ⁹-THC as describedabove for the Crystallizing Step.

In another embodiment, the Δ⁹-THC Purification Method of the presentinvention further comprises allowing the trans-(−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC to crystallize from the first organic composition toprovide crystalline (±)-Δ⁹-THC as described above for the CrystallizingStep, wherein (a) the first organic composition comprises (−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC, and (b) the trans-(−)-Δ⁹-THC is present in firstorganic composition in an amount from about 0.75 to about 1.25 molarequivalents per molar equivalent of trans-(+)-Δ⁹-THC

In another embodiment, the invention relates to a method for makingcrystalline (±)-Δ⁹-THC comprising:

allowing trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC to crystallize from afirst composition comprising trans-(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC, and anon-polar organic solvent to provide crystalline (±)-Δ⁹-THC,

wherein the trans-(−)-Δ⁹-THC and the trans-(+)-Δ⁹-THC were obtained by:

(a) forming a biphasic composition comprising (i) a first organic phasecomprising a first water-immiscible organic solvent, and (ii) analcoholic-caustic phase containing trans-(−)-Δ⁹-THC andtrans-(+)-Δ⁹-THC;

(b) separating the trans-(−)-Δ⁹-THC and the trans-(+)-Δ⁹-THC from thealcoholic-caustic phase; and

(c) forming the first composition comprising (i) the trans-(−)-Δ⁹-THCand the trans-(+)-Δ⁹-THC of step (b), and (ii) the non-polar organicsolvent.

Methods for forming the biphasic composition as well as the amounts andtype of first water-immiscible organic solvent, water-miscible alcohol,water, and alkali metal hydroxide include those described above for theCaustic Contacting Step. Similarly, methods for separating thetrans-(−)-Δ⁹-THC and the trans-(+)-Δ⁹-THC from the alcoholic-causticphase, and methods for forming the first composition comprising (i) thetrans-(−)-Δ⁹-THC and the trans-(+)-Δ⁹-THC of step (b), and (ii) thenon-polar organic solvent include those described above for the(±)-Δ⁹-THC Purification Method.

Once obtained, crystalline (±)-Δ⁹-THC formed in the Crystallizing Stepcan be separated from the liquid phase by methods known in the art.Methods for separating the crystalline (±)-Δ⁹-THC from the liquid phaseinclude, e.g., filtration, centrifugation and decantation. In oneembodiment, crystalline (±)-Δ⁹-THC is separated from the liquid phase byfiltration.

Crystalline (±)-Δ⁹-THC formed in the Crystallizing Step can, optionally,be washed with an organic wash solvent, and separated from the liquidphase as described above. When crystalline (±)-Δ⁹-THC is washed, thetemperature of the organic wash solvent can vary. Typically, thewashing, when done, is carried out with an organic wash solvent at atemperature from about −78° C. to about 50° C.; in another embodiment,from about −30° C. to about 30° C.; and in another embodiment, fromabout −20° C. to about 25° C.

Examples of useful organic wash solvents include the non-polar organicsolvents described above. In one embodiment, the organic wash solvent,when used, is n-heptane.

The separated (±)-Δ⁹-THC can, optionally, be dried. The drying can becarried out at atmospheric pressure, optionally with the aid of a sweepgas such as dry air, nitrogen, helium, argon, or the like.Alternatively, the (±)-Δ⁹-THC can be dried at reduced pressure.

When the separated (±)-Δ⁹-THC is dried, the drying temperature can vary.Typically, the drying, when done, can be carried out at a temperaturefrom about −25° to about 65° C.; in another embodiment, from about 0° toabout 60° C.; and in another embodiment, from about 25° to about 50° C.

Typically, the (±)-Δ⁹-THC obtained in the Crystallizing Step comprisesat least about 95% by weight of trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THCbased on the total amount of cannabinoids. In another embodiment, the(±)-Δ⁹-THC obtained in the Crystallizing Step comprises at least about98% by weight of trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC based on thetotal amount of cannabinoids. In another embodiment, the (±)-Δ⁹-THCobtained in the Crystallizing Step comprises at least about 99% byweight of trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC based on the totalamount of cannabinoids.

The separated (±)-Δ⁹-THC can then be resolved on a chiral stationaryphase as described below in Section 4.4.

4.4. The Resolving Step

In the present invention, (±)-Δ⁹-THC obtained from crystalline(±)-Δ⁹-THC and an eluting solvent are contacted with a chiral stationaryphase to resolve the trans-(−)- and (+)-enantiomers (the “ResolvingStep”). This provides a composition comprising at least about 98% byweight of trans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC based on the total amountof cannabinoids. Without being limited by theory, Applicants believethat resolving (±)-Δ⁹-THC obtained from crystalline (±)-Δ⁹-THC providesa trans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC composition having low levels, ifany, of the cannabinoid impurities found in trans-(−)-Δ⁹-THC ortrans-(+)-Δ⁹-THC obtained by known methods.

The composition comprising (±)-Δ⁹-THC used in the Resolving Step cancontain an amount of trans-(−)-Δ⁹-THC that is less than, equal to orgreater than the amount of trans-(+)-Δ⁹-THC. For example, thecomposition comprising (±)-Δ⁹-THC may be obtained by admixingcrystalline (±)-Δ⁹-THC with a trans-(−)-Δ⁹-THC composition and/or atrans-(+)-Δ⁹-THC prior to carrying out the Resolving Step. Typically,the composition comprising (±)-Δ⁹-THC contains about an equimolar amountof the trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC.

Any known or later-developed chiral stationary phase that resolvestrans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC can be used. For example, a methodfor resolving trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC enantiomers on achiral stationary phase is described in S. L. Levin et al., J.Chromatogr. A 654:53-64 (1993)). Typically, the chiral stationary phasecontains a chiral group or derivative immobilized on a support such as,e.g., a polymer or inorganic oxide. A non-limiting example of a usefulpolymer support is polystyrene in bead form. Non-limiting examples ofuseful inorganic oxide supports include silica, magnesium silicate,magnesia, alumina and molecular sieves. In one embodiment, the inorganicoxide support is silica.

The chiral derivative comprises at least one chiral center. Non-limitingexamples of useful chiral derivatives include tris(arylcarbamate)derivatives of saccharides such as, e.g., amylose, cellulose, chitosin,xylan, curdlan, dextran, and inulan. In one embodiment, the saccharideis amylose.

In one embodiment, the tris(arylcarbamate) istris(3,5-dimethylphenylcarbamate), tris(4-chlorophenylcarbamate),tris(4-methylcarbamate), tris(4-methylbenzoate) ortris[(S)-phenylethylcarbamate]. In another embodiment, thetris(arylcarbamate) is tris(3,5-dimethylphenylcarbamate). In anotherembodiment, the chiral stationary phase is amylosetris(3,5-dimethylcarbonate) immobilized on silica, available asChiralpak® AD™ from Daicel Chemical Industries, Tokyo, Japan.

Other non-limiting examples of useful chiral stationary phases includecellulose triacetate; cellulose tribenzoate;poly[(S)-N-acrylolyphenylalanine ethyl ester];3,5-dinitrobenzoylphenylglycine; crosslinked di-(3,5-dimethylbenzoyl)-Ldiallyltartramide; crosslinked di-(4-tert-butylbenzoyl)-Ldiallyltartramide; and tetrahydro-aminophenanthrene 3,5-dinitrobenzamide(see E. R. Francotte, J. Chromatogr. A 906:379-397 (2001)).

Typically, a concentrated solution of (±)-Δ⁹-THC and an eluting solventis added to the top (or front) of a column containing a chiralstationary phase. The (±)-Δ⁹-THC is then eluted with the eluting solvent(i.e., the mobile phase) to provide eluents containing trans-(−)-Δ⁹-THCor trans-(+)-Δ⁹-THC.

The Resolving Step can be carried using batch chromatography, continuouschromatography or simulated moving bed chromatography (see, e.g., E. R.Francotte, J. Chromatogr. A 906:379-397 (2001)). In one embodiment, theResolving Step is carried using continuous chromatography.

The Resolving Step can be carried out at about 1 atmosphere of pressureor, optionally, at reduced pressure or elevated pressure. In oneembodiment, the Resolving Step is carried out at about 1 atmosphere ofpressure. In another embodiment, the Resolving Step is carried out atelevated pressure. In one embodiment, the Resolving Step is carried outat using flash chromatography at moderately elevated pressure, e.g.,from about 1.1 to about 10 atmospheres; from about 1.1 to about 5atmospheres; or from about 1.1 to about 1.3 atmospheres. In anotherembodiment, the Resolving Step is carried out at using flashchromatography at highly elevated pressure, e.g., from about 10 to about175 atmospheres; from about 100 to about 175 atmospheres; from about 125to about 175 atmospheres; or at about 150 atmospheres.

Non-limiting examples of eluting solvents useful in the Resolving Stepinclude straight-chain or branch-chain (C₁-C₄)alkyls substituted withone or more —OH, —OR₁, —OC(O)R₁, —C(O)OR₁, -halo, or —CN; straight-chainor branch-chain (C₄-C₁₀)aliphatic hydrocarbons; (C₅-C₇)cycloaliphatichydrocarbon optionally substituted with one or more —R₁; (C₄-C₇)cyclicethers optionally substituted with one or more —R₁; aromatichydrocarbons optionally substituted with one or more —R₁, -halo,—CH₂(halo), —CH(halo)₂, —C(halo)₃-O(C₁-C₆)alkyl; or any mixture thereof,where R₁ is (C₁-C₄)alkyl.

Non-limiting examples of straight-chain or branch-chain (C₁-C₄)alkylssubstituted with one or more —OH, —OR₁, —OC(O)R₁, —C(O)OR₁, -halo, or—CN include methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, tert-butanol, chloromethane, methylene chloride, chloroform,carbon tetrachloride chloride, diethyl ether, di-isopropyl ether,tert-butyl methyl ether, acetonitrile, methyl formate, ethyl formate,methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, or anymixture thereof.

Non-limiting examples of straight-chain or branch-chain(C₄-C₁₀)aliphatic hydrocarbons include butane, pentane, hexane, heptane,isooctane, nonane, decane, or any mixture thereof.

Non-limiting examples of (C₅-C₇)cycloaliphatic hydrocarbons optionallysubstituted with one or more —R₁ include cyclopentane, cyclohexane,methylcyclohexane, cycloheptane or any mixture thereof.

Non-limiting examples of (C₄-C₇)cyclic ethers optionally substitutedwith one or more —R₁ include tetrahydrofuran, methyltetrahydrofuran,1,4-dioxane, 1,3-dioxolane, or any mixture thereof.

Non-limiting examples of aromatic hydrocarbons optionally substitutedwith one or more —R₁, -halo, —CH₂(halo), —CH(halo)₂,—C(halo)₃-O(C₁-C₆)alkyl include toluene, xylene, chlorobenzene,benzotrifluoride, or any mixture thereof.

In one embodiment, the eluting solvent comprises an aliphatichydrocarbon and an alcohol. In another embodiment, the eluting solventcomprises n-heptane and iso-propanol. In another embodiment, the organicsolvent comprises a (95:5 (v/v) mixture of n-heptane:2-propanol.

The progress of the Resolving Step can be monitored using analyticalmethods described above in Section 4.3.

The eluents containing trans-(−)-Δ⁹-THC and being substantially free ofother cannabinoids can be combined. In one embodiment, the eluentscomprise at least about 98% by weight of trans-(−)-Δ⁹-THC; in anotherembodiment, at least about 99% by weight of trans-(−)-Δ⁹-THC; in anotherembodiment, at least about 99.5% by weight of trans-(−)-Δ⁹-THC; and inanother embodiment, at least about 99.9% by weight of trans-(−)-Δ⁹-THCbased on the total amount of trans-(−)-Δ⁹-THC and trans-(+)-Δ⁹-THC.

Similarly, eluents containing trans-(+)-Δ⁹-THC and being substantiallyfree of other cannabinoids can be combined. In one embodiment, theeluents comprise at least about 98% by weight of trans-(+)-Δ⁹-THC; inanother embodiment, at least about 99% by weight of trans-(+)-Δ⁹-THC; inanother embodiment, at least about 99.5% by weight of trans-(+)-Δ⁹-THC;and in another embodiment, at least about 99.9% by weight oftrans-(+)-Δ⁹-THC based on the total amount of trans-(+)-Δ⁹-THC andtrans-(−)-Δ⁹-THC.

The eluents comprising a first solvent and trans-(−)-Δ⁹-THC ortrans-(+)-Δ⁹-THC can, optionally, be separated from the volatiles toprovide each enantiomer as an oil. Methods for separating thetrans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC from volatile components include,e.g., distillation at atmospheric pressure or reduced pressure. Forexample, the trans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC can, if desired, bedistilled by fractional distillation to provide a trans-(−)-Δ⁹-THC ortrans-(+)-Δ⁹-THC distillate (see U.S. Pat. No. 4,381,399 to Olsen etal.).

4.5. Compositions Comprising Trans-(−)-Δ⁹-THC or Trans-(+)-Δ⁹-THC

As noted above, the present invention also relates to compositionscomprising trans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC.

In one embodiment, the invention relates to a composition comprising atleast 99.0% by weight of trans-(−)-Δ⁹-THC; in another embodiment, atleast about 99.5% by weight of trans-(−)-Δ⁹-THC; and in anotherembodiment, at least 99.9% by weight of trans-(−)-Δ⁹-THC based on thetotal amount of cannabinoids.

In one embodiment, the invention relates to a composition comprising atleast 99.0% up to about 99.95% by weight of trans-(−)-Δ⁹-THC based onthe total amount of cannabinoids. In another embodiment, the inventionrelates to a composition comprising at least 99.0% up to about 99.98% byweight of trans-(−)-Δ⁹-THC based on the total amount of cannabinoids.

In another embodiment, the compositions comprising at least 99.0% byweight of trans-(−)-Δ⁹-THC based on the total amount of cannabinoids areformulated as a pharmaceutical composition as described in Section 4.6.

In one embodiment, the invention relates to a composition comprising atleast 99.0% by weight of trans-(+)-Δ⁹-THC; in another embodiment, atleast 99.0.0% by weight of trans-(+)-Δ⁹-THC; in another embodiment, atleast 99.5.0% by weight of trans-(+)-Δ⁹-THC; and in another embodiment,at least 99.9% by weight of trans-(+)-Δ⁹-THC based on the total amountof cannabinoids.

The trans-(−)-Δ⁹-THC compositions of the present invention typicallycontain no Δ⁹-THC carboxylic acid, which can be found intrans-(−)-Δ⁹-THC compositions derived from natural sources (see R. F.Turk et al., J. Pharm. Pharmac. 23:190-195 (1971)). In one embodiment,the trans-(−)-Δ⁹-THC compositions of the present invention contain lessthan 0.05% Δ⁹-THC carboxylic acid; in another embodiment, less than0.01% Δ⁹-THC carboxylic acid; in another embodiment, less than 0.005%Δ⁹-THC carboxylic acid; and in another embodiment, less than 0.001%Δ⁹-THC carboxylic acid based on the based on the total amount ofcannabinoids. In another embodiment, the trans-(−)-Δ⁹-THC compositionscontain no Δ⁹-THC carboxylic acid.

In another embodiment, the invention relates to a composition comprisingat least 99.0% by weight of trans-(−)-Δ⁹-THC and less then of 0.05% ofΔ⁹-THC carboxylic acid; in another embodiment, at least about 99.5% byweight of trans-(−)-Δ⁹-THC and less then 0.05% of Δ⁹-THC carboxylicacid; and in another embodiment, at least 99.9% by weight oftrans-(−)-Δ⁹-THC and less then 0.05% of Δ⁹-THC carboxylic acid based onthe total amount of cannabinoids.

In another embodiment, the invention relates to a composition comprisingat least 99.0% by weight of trans-(+)-Δ⁹-THC and less then of 0.05% ofΔ⁹-THC carboxylic acid; in another embodiment, at least about 99.5% byweight of trans-(+)-Δ⁹-THC and less then 0.05% of Δ⁹-THC carboxylicacid; and in another embodiment, at least 99.9% by weight oftrans-(+)-Δ⁹-THC and less then 0.05% of Δ⁹-THC carboxylic acid based onthe total amount of cannabinoids.

As noted above, trans-(+)-Δ⁹-THC, together with trans-(−)-Δ⁹-THC, isuseful for making crystalline (±)-Δ⁹-THC.

The trans-(−)-Δ⁹-THC or trans-(+)-Δ⁹-THC compositions can be made bymethods described above.

In another embodiment, the invention relates to a composition comprising(−)-Δ⁹-THC, trans-(+)-Δ⁹-THC, a first water-immiscible organic solvent,a water-miscible alcohol, water, and an alkali metal hydroxide. Thecomposition is useful for removing impurities from (−)-Δ⁹-THC and/ortrans-(+)-Δ⁹-THC.

4.6. Therapeutic/Prophylactic Administration of Compositions ComprisingTrans-(−)-Δ⁹-THC

The compositions of the invention comprising at least 99.0% by weight oftrans-(−)-Δ⁹-THC based on the total amount of cannabinoids are usefulfor treating the same diseases, ailments, or disorders (“Conditions”)for which trans-(−)-Δ⁹-THC is known to be useful, or for any Conditionfor which trans-(−)-Δ⁹-THC is later found to be useful for treating orpreventing. For example, trans-(−)-Δ⁹-THC compositions comprising atleast 99.0% by weight of trans-(−)-Δ⁹-THC based on the total amount ofcannabinoids can be used for treating or preventing emesis, loss ofweight loss of appetite, multiple sclerosis, Tourette's syndrome,Parkinson's disease, or palsies such as cerebral palsy. Accordingly, inone embodiment, the present invention also relates to methods fortreating or preventing a Condition, comprising administering to apatient in need thereof an effective amount of a trans-(−)-Δ⁹composition, wherein the trans-(−)-Δ⁹-THC composition comprises at least99.0% by weight of trans-(−)-Δ⁹-THC; in another embodiment at least99.0% by weight of trans-(−)-Δ⁹-THC; in another embodiment at least99.5% by weight of trans-(−)-Δ⁹-THC; and in another embodiment at least99.9% by weight of trans-(−)-Δ⁹-THC based on the total amount ofcannabinoids.

In another embodiment, the present invention also relates to methods fortreating or preventing a Condition, comprising administering to apatient in need thereof an effective amount of a trans-(−)-Δ⁹composition, wherein the trans-(−)-Δ⁹-THC composition comprises at least99.0% by weight of trans-(−)-Δ⁹-THC and less then 0.05% of Δ⁹-THCcarboxylic acid; in another embodiment at least 99.0% by weight oftrans-(−)-Δ⁹-THC and less then 0.05% of Δ⁹-THC carboxylic acid; inanother embodiment at least 99.5% by weight of trans-(−)-Δ⁹-THC and lessthen 0.05% of Δ⁹-THC carboxylic acid; and in another embodiment at least99.9% by weight of trans-(−)-Δ⁹-THC based on the total amount ofcannabinoids and less then 0.05% of Δ⁹-THC carboxylic acid.

In one embodiment, the Condition is pain.

In another embodiment, the Condition is emesis, e.g., as the result ofcancer chemotherapy.

In another embodiment, the Condition is loss of appetite.

In another embodiment, the Condition is weight loss, e.g., as the resultof symptomative HIV infection including acquired immunodeficiencysyndrome (AIDS) or AIDS related complex (ARC).

When administered to a patient, the trans-(−)-Δ⁹-THC compositionscontaining at least about 99.0% by weight of trans-(−)-Δ⁹-THC based onthe total amount of cannabinoids comprise a suitable amount of apharmaceutically acceptable carrier so as to provide the form for properadministration to the patient.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient, or vehicle withwhich the trans-(−)-Δ⁹-THC, containing at least about 99.0% by weight oftrans-(−)-Δ⁹-THC based on the total amount of cannabinoids, isadministered. Such pharmaceutical carriers can be liquids, such as waterand oils, including those of petroleum, animal, vegetable or syntheticorigin, such as peanut oil, soybean oil, mineral oil, sesame oil, andthe like. The pharmaceutical carriers can be saline, gum acacia,gelatin, starch paste, talc, keratin, colloidal silica, urea, and thelike. In addition, auxiliary, stabilizing, thickening, lubricating andcoloring agents may be used. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, and/or pHbuffering agents. When administered to a patient, the pharmaceuticallyacceptable carriers are preferably sterile.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse.

In one embodiment, the trans-(−)-Δ⁹-THC composition containing at leastabout 99.0% by weight of trans-(−)-Δ⁹-THC based on the total amount ofcannabinoids further comprises sesame oil. In another embodiment, thetrans-(−)-Δ⁹-THC compositions containing at least about 99.0% by weightof trans-(−)-Δ⁹-THC based on the total amount of cannabinoids furthercomprises sesame oil, and the resultant admixture is encapsulated (see,e.g., U.S. Pat. No. 6,703,418 B2).

In another embodiment, the trans-(−)-Δ⁹-THC composition containing atleast about 99.0% by weight of trans-(−)-Δ⁹-THC based on the totalamount of cannabinoids is formed as a tablet.

The trans-(−)-Δ⁹-THC compositions containing at least about 99.0% byweight of trans-(−)-Δ⁹-THC based on the total weight of cannabinoids canbe administered by any convenient route, for example by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and maybe administered together with another biologically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., and can be used to administer the pharmaceuticalcompositions. Methods of administration include but are not limited tointradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intranasal, intracerebral,intravaginal, transdermal, rectally, by inhalation, or topically to theears, nose, eyes, or skin. The preferred mode of administration is oral,but other modes of administration can be left to the discretion of thepractitioner.

When used for oral delivery, the trans-(−)-Δ⁹-THC composition containingat least about 99.0% by weight of trans-(−)-Δ⁹-THC based on the totalamount of cannabinoids can be in the form of tablets, lozenges, aqueousor oily suspensions, granules, powders, emulsions, capsules, syrups, orelixirs, for example. Orally administered compositions can contain oneor more optional agents, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,to provide a pharmaceutically palatable preparation. Moreover, where intablet or pill form, the compositions can be coated to delaydisintegration and absorption in the gastrointestinal tract therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administeredpharmaceutical compositions. In these later platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero-orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard carriers such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such carriersare preferably of pharmaceutical grade.

When used for intravenous delivery, the trans-(−)-Δ⁹-THC compositioncontaining at least about 99.0% by weight of trans-(−)-Δ⁹-THC based onthe total amount of cannabinoids is formulated in accordance withroutine procedures for intravenous administration to human beings.Preferably, the pharmaceutical compositions for intravenousadministration are solutions in sterile isotonic aqueous buffer,optionally with a solublizing agent. Compositions for intravenousadministration may optionally include a local anesthetic such aslignocaine to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampoule orsachette indicating the quantity of active agent. Where thepharmaceutical compositions are to be administered by infusion, they canbe dispensed, for example, with an infusion bottle containing sterilepharmaceutical grade water or saline, optionally with a solublizingagent. Where the pharmaceutical compositions are administered byinjection, an ampoule of sterile water for injection or saline can beprovided so that the ingredients can be mixed prior to administration.

The amount of the trans-(−)-Δ⁹-THC composition containing at least about99.0% by weight of trans-(−)-Δ⁹-THC based on the total amount ofcannabinoids that is effective in the treatment or prevention of aCondition can be determined by standard clinical techniques. Inaddition, in vitro or in vivo assays can optionally be employed to helpidentify optimal dosage amounts. The precise dose to be employed willalso depend on the route of administration, and the seriousness of theCondition and can be decided according to the judgment of a practitionerand/or each animal's circumstances. When trans-(−)-Δ⁹-THC compositionscontaining at least about 99.0% by weight of trans-(−)-Δ⁹-THC based onthe total amount of cannabinoids are administered orally, the effectivedosage amount is from about 0.005 mg/kg of body weight to about 0.4mg/kg of body weight about every 4 hours, although it is typically about0.1 mg/kg of body weight or less. In one embodiment, the effectivedosage amount is from about 0.005 mg/kg of body weight to about 0.4mg/kg of body weight; in another embodiment, the effective dosage amountis from about 0.01 mg/kg of body weight to about 0.1 mg/kg of bodyweight; and in another embodiment, the effective dosage amount is fromabout 0.01 mg/kg of body weight to about 0.075 mg/kg of body weight.

The oral dosage forms typically comprise an amount of trans-(−)-Δ⁹-THCfrom about 0.1 mg to about 20 mg; in another embodiment, from about 2.5mg to about 10 mg; in another embodiment, about 2.5 mg; in anotherembodiment, about 5 mg; and in another embodiment, about 10 mg.

In one embodiment, an effective dosage amount is administered aboutevery 24 hours until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 12 hours until theCondition is abated. In another embodiment, an effective dosage amountis administered about every 8 hours until the Condition is abated. Inanother embodiment, an effective dosage amount is administered aboutevery 6 hours until the Condition is abated. And in another embodiment,an effective dosage amount is administered about every 4 hours until theCondition is abated.

In certain embodiments, it may be desirable to introduce thepharmaceutical compositions into the central nervous system by anysuitable route, including intraventricular and intrathecal injection.Intraventricular injection may be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the pharmaceutical compositions can be formulatedas a suppository, with traditional binders and carriers such astriglycerides.

In another embodiment, the trans-(−)-Δ⁹-THC composition containing atleast about 99.0% by weight of trans-(−)-Δ⁹-THC based on the totalamount of cannabinoids can be delivered in a vesicle, in particular aliposome (see Langer, Science 249:1527-1533 (1990); Treat et al., inLiposomes in the Therapy of Infectious Disease and Cancer,Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989);Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).

In yet another embodiment, the trans-(−)-Δ⁹-THC composition containingat least about 99.0% by weight of trans-(−)-Δ⁹-THC based on the totalamount of cannabinoids can be delivered in a controlled-release system.In one embodiment, a pump can be used (see Langer, supra; Sefton, CRCCrit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507(1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In anotherembodiment, polymeric materials can be used (see Medical Applications ofControlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla.(1974); Controlled Drug Bioavailability, Drug Product Design andPerformance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger andPeppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see alsoLevy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351(1989); Howard et al., J. Neurosurg. 71:105 (1989)). In anotherembodiment, a controlled-release system can be placed in proximity ofthe target of the pharmaceutical compositions, thus requiring only afraction of the systemic dose (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).Other controlled-release systems discussed in the review by Langer(Science 249:1527-1533 (1990)) can be used.

The invention also provides pharmaceutical packs or kits comprising oneor more containers filled with the trans-(−)-Δ⁹-THC compositioncontaining at least about 99.0% by weight of trans-(−)-Δ⁹-THC based onthe total amount of cannabinoids. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use or sale for human administration.

The following examples are set forth to assist in understanding theinvention and do not limit the invention described and claimed herein.Such variations of the invention, including the substitution of allequivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulations orminor changes in experimental design, fall within the scope of thepresent invention.

5. EXAMPLES

Unless otherwise stated, all reactions were carried out under argon ornitrogen atmosphere.

Unless otherwise stated, the phrase “cold water,” “cold hexane,” or“cold heptane” means water, hexane, or heptane, respectively, at atemperature of from about 0° to about 5° C.

Reagents and Solvents: Unless otherwise stated, all reagents andsolvents were purchased from Aldrich Chemical Company and used withoutfurther purification.

High Performance Liquid chromatography: High performance liquidchromatography (HPLC) was carried out under the following conditions,and the purity of the samples eluents was calculated from the resultantarea percentages:

Standard HPLC was carried out using a 3 μm C₁₈-stationary phase column(150×4.6 mm); a mobile phase of the following composition: THF (71%),MeOH (24%) and water (5%) for 25 min, gradient to THF (71%), MeOH (5%)and water (24%) in 10 min, and THF (71%), MeOH (24%) and water (5%) for10 min; a flow rate of 1 mL/min; and a UV detector at 228 nm.

Chiral HPLC method 1 was carried out using a 20 μm Chiralpak AD 250×4.6mm column; a mobile phase of heptane:isopropanol (95:5 (v:v)); a flowrate of 1 mL/min; and a UV detector at 228 nm. The concentration of thesample was about 1 mg per 1 mL of heptane.

Chiral HPLC method 2 was carried out using a 5 μm Chiralpak AD-H 250×4.6mm (Diacel) column; a mobile phase of hexane:ethanol (95:5 (v:v)) forCBD and hexane:isopropanol (90:10 (v:v)) for Δ⁹-THC; a flow rate of 1mL/min; and a UV detector at 228 nm. The concentration of the sample wasabout 1 mg per 1 mL of hexane.

Gas chromatography: Gas chromatography (GC) was carried out under thefollowing conditions, and the purity of the eluents was calculated fromthe resultant area percentages:

Standard GC was carried using a HP-5 capillary column (length—30 m,ID—0.25 mm); a stationary phase of 5% diphenyl/95% dimethyl)polysiloxane(0.25 μm film); an injection temperature of 230° C.; adetector/temperature (FID) of 270° C.; and an oven temperature programusing a hold at 100° C. for 3 min, increasing to 240° C. at 10° C. perminute, holding at 240° C. for 10 min, increasing to 270° C. per min,and holding at 270° C. for 10 min. The concentration of the GC samplewas about 1 mg per 1 mL of EtOH.

Chiral GC was carried out in a manner similar to that described abovefor standard GC, except that an Alpha-DEX-120, 30 m×0.25 mm column wasused; the injection temperature was 250° C.; and the oven temperaturewas 90° C. (isothermal).

Powder x-ray diffraction patterns: Powder x-ray diffraction analysis wascarried out by known methods using a PANALYTICAL (Philips) X'Pert ProMPD x-ray powder diffraction system (CuK_(α) radiation, PW3050/60goniometer, PW3011/20 proportional detector). The Bragg-Brentano schemewas used for beam focusing.

Nuclear Magnetic Resonance Spectroscopy: Nuclear magnetic resonance(NMR) spectra were recorded on a Bruker AM-200 (¹H at 200 MHz, ¹³C at 50MHz) or a Bruker AM-400 (¹H at 400 MHz) instruments using CDCl₃ (unlessotherwise stated) as a solvent. Chemical shifts are in δ (ppm) relativeto internal TMS.

Melting points: Melting point determinations were carried out in opencapillary tubes using a Buchi B-545 capillary melting point apparatus orwith a Mettler-Toledo FP-81 Melting point accessory with FP-900processor. The melting points are uncorrected.

5.1. Example 1 Synthesis of (−)-cis-p-Menth-2,8-dien-1-ol

Preparation of (−)-(1R,2R,S5)-2-phenylthio-8-p-menthen-1-ol: A mixtureof (−)-limonene oxide (152.2 g, 1.00 mol (about 1:1 cis:transdiastereomeric mixture) (Aldrich Chemical), thiophenol (60.6 g, 0.55mol) (Fluka Chemical, Buchs, Switzerland), potassium carbonate (82.9 g,0.60 mol), N,N-dimethylformamide (18.9 g, 0.26 mol) and toluene (400 mL)was stirred at 117° C. for 19 hours under an Ar atmosphere. The mixturewas cooled to 25° C. and water (300 mL) was added. The resultant organicphase was collected, and the water layer was extracted with toluene(3×200 mL). The combined organic phases were washed with water (1×400mL) and a 15% solution of brine (1×410 mL). The organic phase was thendried over Na₂SO₄ (30 g), filtered, and the resultant filtrateconcentrated under pressure at 65° C. The resultant brown oil (200.5 g)was fractionally distilled under reduced pressure to provide(−)-cis-limonene oxide (33.7 g) (28.1° to 32.1° C. @ 1.1 mbar) and(−)-(1R,2R,4S)-2-phenylthio-8-p-menthen-1-ol (147.4 g) (128.1° to 138.2°C. @ 1.2 mbar) having a purity (GC) of 90.2%. An analytical sample of(−)-(1R,2R,4S)-2-phenylthio-8-p-menthen-1-ol had mp of 50-51° C.(hexane) and a purity (GC) of 99.0%.

Optical rotation: [α]_(D) ²⁰−110° (c=1.55, CHCl₃).

¹H NMR agreed with the structure.

Preparation of (1R,2R,4S)-1-Hydroxy-8-p-menthen-2-phenylsulfoxide:(−)-(1R,2R,4S)-2-phenylthio-8-p-menthen-1-ol (147 g; 0.56 mol) wasdissolved in methyl alcohol (1.35 L) with stirring at 25° C. under an Aratmosphere, and the resultant solution was cooled to −10° to −5° C. Asolution of OXONE® (potassium peroxymonosulfate) (279.1 g, 0.448 mol)(Aldrich Chemical) in water (1.35 L) was added dropwise to the methylalcohol solution over 2 hours at −10° to −5° C., and the resultantmixture was stirred for an additional 30 min at −10° to −5° C. Themixture was warmed to 20° to 25° C., water (2.1 L) was added, and theresultant biphasic mixture was extracted with dichloromethane (3×910mL). The combined organic phases were dried over sodium sulfate andfiltered, and the resultant filtrate was concentrated under reducedpressure at 60° C. to provide 150.9 g of a residue. The residue was thenpurified by chromatography on a silica gel column (eluent:n-heptane/ethyl acetate 9:1 then 8:2). The fractions containing mainly(1R,2R,4S)-1-hydroxy-8-p-menthen-2-phenyl sulfoxide were combined andconcentrated under vacuum for 10 hours at 40° to 50° C. to provide(1R,2R,4S)-1-hydroxy-8-p-menthen-2-phenyl sulfoxide as a mixture of twodiastereomers. Yield: 86.1 g; 55.2%. The product was stored in freezer.

(−)-cis-p-Mentha-2,8-dien-1-ol: A mixture of(1R,2R,4S)-1-hydroxy-8-p-menthen-2-phenylsulfoxide (86 g, 0.31 mol) andpiperidine (71.0 g, 0.83 mol) in dimethylsulfoxide (910 mL) was heatedto 163° C. under a flowing Ar atmosphere, and the resultant mixture wasstirred at 163° C. for 3 hours. The mixture was cooled to 20° to 25° C.,treated with water (800 ml), and extracted with diethyl ether (2×400mL). The combined organic phases were washed with 1N HCl (160 mL), a 7%solution of sodium hydrogen carbonate (150 mL), brine (150 mL), anddried over sodium sulfate. The organic phase was then concentrated underreduced pressure. The resultant residue (93.3 g) was purified by silicagel column chromatography (eluent: n-heptane followed by n-heptane:ethylacetate (1:9 (v:v)), the fractions containing mainly(−)-cis-p-mentha-2,8-dien-1-ol were combined and concentrated underreduced pressure at 40° to 50° C. over 10 hours to provide(−)-cis-p-mentha-2,8-dien-1-ol.

Yield: 26.1 g; 55%. Analysis (GC) of the product indicated that it was90.9% pure.

Optical rotation: [α]_(D) ²⁵−69° (neat).

¹H NMR agreed with the structure.

5.2. Example 2 Synthesis of (+)-cis-p-Menth-2,8-dien-1-ol

(+)-p-mentha-2,8-dien-1-ol was prepared as described in Example 1,except that (+)-limonene oxide (1:1 cis/trans diastereomeric mixture)was used instead of (−)-limonene oxide. Analysis (GC) of the resultantproduct indicated that it had a purity of 91.0%.

Optical rotation: [α]_(D) ²⁵+78° (neat).

5.3. Example 3 Synthesis of (±)-cis-p-Menth-2,8-dien-1-ol

(±)-p-Mentha-2,8-dien-1-ol was prepared by mixing equivalent quantitiesof (−)-p-mentha-2,8-dien-1-ol of Example 2 with(+)-p-mentha-2,8-dien-1-ol of Example 1.

5.4. Example 4 Synthesis of (±)-CBD

Synthesis of crude (+)-CBD (3b): A mixture of olivetol (3.6 g, 20 mmol),zinc chloride (3.5 g, 26 mmol), water (3.5 mL, 19 mmol) anddichloromethane (35 mL) was refluxed for 1 hour. A solution of(−)-p-mentha-2,8-dien-1-ol (3.0 g, 20 mmol) in dichloromethane (10 mL)was added drop-wise over 0.75 hour to the refluxing mixture, and theresultant reaction mixture was mixed for 0.5 hours at reflux. Themixture was cooled to 25° C., ice water (50 mL) was added, and theresultant biphasic mixture stirred for 20 minutes at 0° C. The resultantorganic phase was collected, washed with water (2×20 mL) and 5% NaHCO₃(20 mL). The organic phase was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide 6.0 g of first crude(+)-CBD residue. Analysis (GC) of the first crude (+)-CBD residueindicated that it contained (+)-CBD (46.9%) and abn-(−)-CBD (19.7%). Thefirst crude (+)-CBD residue was purified by column chromatography onsilica gel (eluent MTBE/hexane) to provide 2.4 g of a second crude(+)-CBD residue.

Synthesis of (+)-CBD-bis(3,5-dinitrobenzoate)(4b): A solution of3,5-dinitrobenzoyl chloride (3.4 g, 14.7 mmol) in dichloromethane (10mL) was added dropwise to a stirred mixture of the second crude (+)-CBDresidue (2.4 g), 4,N,N-dimethylaminopyridine (0.05 g), pyridine (6 mL)and dichloromethane (15 mL) at 0° to 5° C. The mixture was allowed towarm to 25° C. and stirred for 2 hour at 25° C. The mixture was thenpoured into a mixture of 37% HCl (6 mL), ice (75 g) and dichloromethane(50 mL). The resultant organic phase was collected, washed with brine(15 mL), 5% NaHCO₃ (15 mL), dried over Na₂SO4, and filtered. Theresultant filtrate was concentrated under reduced pressure to provide5.2 g of crude (+)-CBD-bis(3,5-dinitrobenzoate) (4b). A solution of thecrude (+)-CBD-bis(3,5-dinitrobenzoate) (5.2 g) in a 10:1 (vol:vol)mixture of isopropanol and ethylacetate (70 mL) was stirred overnight at25° C. and filtered. The resultant precipitate was washed with 10:1(vol:vol) mixture of isopropanol and ethylacetate (3×10 mL) and driedunder reduced pressure to provide crystalline(+)-CBD-bis(3,5-dinitrobenzoate) (4b). Yield: 3.7 g, 26.5%.

Melting point: 90-92° C. (dec.).

Optical rotation: [α]_(D) ²⁰+80° (c=0.4, CHCl₃).

Synthesis of (+)-CBD (3b): A mixture of the crystalline (+)-CBDbis(3,5-dinitrobenzoate) (4b) (3.5 g, 5.0 mmol), butylamine (3.7 g, 50mmol) and toluene (20 mL) was stirred at room temperature for 12 hoursand concentrated under reduced pressure. The resultant residue waspurified by column chromatography on silica gel (eluent hexane:MTBE(70:1 (v:v)) to provide 1.3 g of (+)-CBD as an oil. A solution of the(+)-CBD (1.3 g) in hexane (1 mL) was kept overnight at −15° C. Theresultant mixture was then filtered, and the resultant solids were driedunder reduced pressure to provide (+)-CBD (3b) as white crystals. Yield:1.2 g, 64%. Analysis (GC) of the product indicated that it was 98.6%pure.

Melting point: 64-66° C.

Optical rotation: [α]_(D) ²⁰: +126° (c=0.12, 95% EtOH).

5.5. Example 5 Preparation of (±)-Δ⁸-THC

A solution of methanesulfonic acid (1.1 g, 11 mmol) in dichloromethane(6 mL) was added to solution of olivetol (10.0 g, 55.5 mmol) and(±)-p-mentha-2,8-dien-1-ol (8.5 g, 55.5 mmol) in dichloromethane (130mL). The resultant mixture was refluxed for 4 hours with removal ofwater using a Dean-Stark separator. The mixture was then cooled to 25°C. and treated with aqueous NaHCO₃. The resultant organic phase wascollected and concentrated under reduced pressure. The resultant residuewas dissolved in heptane (110 mL) and washed with 10% NaOH (130 mL), andthe resultant organic phases was concentrated under reduced pressure toprovide 15.6 g of crude (±)-Δ⁸-THC. Analysis (GC) of the crude productindicated that it had a purity of 61.7%.

5.6. Example 6 Preparation of (−)-Δ⁸-THC

Crude (−)-Δ⁸-THC (2a) was prepared in a manner similar to that describedin Example 5 for the preparation of crude (±)-Δ⁸-THC, except that(+)-p-mentha-2,8-dien-1-ol was used instead of(±)-p-mentha-2,8-dien-1-ol.

5.7. Example 7 Preparation of (+)-Δ⁸-THC

Crude (+)-Δ⁸-THC (2b) was prepared in a manner similar to that describedin Example 5 for the preparation of crude (±)-Δ⁸-THC, except that(−)-p-mentha-2,8-dien-1-ol was used instead of(±)-p-mentha-2,8-dien-1-ol.

5.8. Example 8 Two-Part Synthesis of Trans-(−)-Δ⁹-THC

Synthesis of (−)-CBD (3a): A solution of (+)-p-mentha-2,8-dien-1-ol(84.5 g, 0.56 mol) in dichloromethane (325 mL) was added drop-wise over1 hour to a stirred mixture of olivetol (100.0 g, 0.56 mol), zincchloride (100.3 g, 0.72 mol), water (10.0 mL, 0.56 mol) anddichloromethane (1 L) at 40° C. The mixture was stirred for anadditional 30 minutes at 40° C. The mixture was cooled to 25° C., pouredinto ice water (500 g), and the resultant biphasic mixture stirred for20 minutes at 0° C. The resultant organic phase was collected and washedwith cold water (2×250 mL). The organic phase was collected andconcentrated under reduced pressure to provide a first residue (185.5g). Analysis (GC) of the first residue indicated that it contained(−)-CBD (51.8%), abn-CBD (13.2%), olivetol (8.0%) and dialkylatedolivetol (13.4%).

The first residue (185.5 g) was dissolved in n-heptane (1.1 L), and theresultant solution was admixed with a solution of 10% sodium hydroxide(1.3 L). The resultant organic phase was collected, washed with water(250 mL), and concentrated under reduced pressure to provide anoily-brown second residue (124.3 g). Analysis (GC) of the second residueindicated that it contained (−)-CBD (66.0%), abn-CBD (0.0%), olivetol(0.0%) and dialkylated olivetol (16.8%).

The second residue (124.3 g) was fractionally distilled (171°-178° C.;0.1 mm Hg) to provide a 87.0 g of a distillate. Analysis (GC) of thedistillated indicated that it contained 74.3% of (−)-CBD.

The distillate (87.0 g) was dissolved in heptane (425 mL) at 57° C. andfiltered. The resultant filtrate was cooled to 0° to 5° C. and seededwith ˜0.02 mg of powdered crystalline (−)-CBD (3a). The seeded solutionwas stirred at 0° to 5° C. for 5 hours then at −15° to −20° C. for 48hours. The resultant mixture was filtered, and the resultant solids werewashed with cold heptane. The solids were then dried under reducedpressure at 40° C. to provide (−)-CBD (3a). Yield: 39.2 g; 22%. Analysis(GC) of the product indicated that it contained (−)-CBD (3a) (97.1%) andtrans-(−)-Δ⁹-THC (1a) (1.44%). The structure of 3a was confirmed by ¹HNMR spectroscopy. An analytical sample was prepared by recrystallizing aportion of the crude 3a from heptane as described above.

Melting point: 64°-65° C.

Optical rotation: [α]_(D) ²⁰−132° (c=0.12, 95% EtOH).

Synthesis of trans-(−)-Δ⁹-THC (1a): A solution of 15.0 g (47.8 mmol) ofthe crystallized (−)-CBD (3a) in anhydrous dichloromethane (45 mL) wasadded drop-wise over 1 hour to a stirred solution of BF₃.Et₂O (8.4 g,59.2 mmol) in anhydrous dichloromethane (180 mL) at −10° C. under an Aratmosphere. The mixture was stirred for 2 hours at −10° C. and pouredinto ice water (100 g). The resultant biphasic mixture was furtherstirred for 20 minutes at 0° C. The resultant organic phase wascollected, washed with cold water (50 mL), 7% aqueous sodium bicarbonate(50 mL), and water (50 mL). The organic phase was dried with Na₂SO₄ andfiltered. The resultant filtrate was concentrated under reduced pressureat 40° C. to provide trans-(−)-Δ⁹-THC (1a) as a yellow oil. Yield: 14.9g, 99%. Analysis (CG) of the product indicated that it contained 81.9%of trans-(−)-Δ⁹-THC (1a).

5.9. Example 9 One-Pot Synthesis of Trans-(−)-Δ⁹-THC

A mixture of olivetol (50.0 g, 0.28 mol), zinc chloride (50.0 g, 0.36mol) and anhydrous dichloromethane (510 mL) was stirred at 40° C. for 1hour under an Ar atmosphere. A solution of (+)-p-mentha-2,8-dien-1-ol(42.2 g, 0.28 mol) and dichloromethane (155 mL) was added drop-wise over1 hour to the stirred olivetol-containing mixture, and the resultantmixture was stirred for an additional 40 minutes at 40° C. The mixturewas cooled to −10° C., and a solution of BF₃Et₂O (23.6 g, 166 mmol) inanhydrous dichloromethane (37 mL) was added dropwise over one hour. Theresultant mixture was stirred for 1.5 hours at −10° C. Cold water (250mL) was added, and the resultant organic phase was collected and washedwith cold water (120 mL), 7% aqueous sodium bicarbonate (120 mL), andwater (120 mL). The organic phase was dried with Na₂SO₄ (30 g) andfiltered. The resultant filtrate was concentrated under reduced pressureto provide trans-(−)-Δ⁹-THC (1a) as a brown oil.

Yield: 89.14 g, 46% based on the trans-(−)-Δ⁹-THC content in the oil.Analysis (GC) of the product indicated that it containedtrans-(−)-Δ⁹-THC (1a) (45.1%), (−)-Δ⁸-THC (5.06%) (2a), (−)-Δ⁸-iso-THC(17.6%), CBD (3a) (0.71%), olivetol (7.95%) and dialkylated olivetol(10.8 wt. %); no trans-(+)-Δ⁹-THC (1b) was detected.

A solution of the trans-(−)-Δ⁹-THC oil (20.0 g) in heptane (120 mL) wasthoroughly washed with 10% NaOH (150 mL) and water (50 mL), dried overNa₂SO₄, and filtered. The resultant filtrate was then concentrated underreduced pressure to provide a first crude residue (16.6 g) containing38.5 wt. % of trans-(−)-Δ⁹-THC (1a) using HPLC; and trans-(−)-Δ⁹-THC(1a) (47.4%), Δ⁸-THC (2a) (8.6%), Δ⁸-iso-THC (19.6%), CBD (0.5%),olivetol (0.0%) and dialkylated olivetol (10.9%) using GC.

A solution of the first crude residue (16.5 g) in heptane (240 mL) wasextracted with an aliquot of 9% NaOH in 80% methanol (3×180 mL). Thecombined basic methanolic extracts were acidified to approximately pH 7with 20% citric acid and extracted with heptane (3×90 mL). The combinedorganic fractions were washed with water (50 mL), dried over Na₂SO₄, andfiltered. The resultant filtrate was then concentrated under reducedpressure to provide 13.7 g of crude residue which contained 44.0 wt. %of trans-(−)-Δ⁹-THC using HPLC; and trans-(−)-Δ⁹-THC (1a) (51.8%),Δ⁸-THC (2a) (10.0%), Δ⁸-iso-THC (22.3%), CBD (0.0%), olivetol (0.0%) anddialkylated olivetol (1.3%) using GC.

5.10. Example 10 Synthesis of Trans-(+)-Δ⁹-THC

A solution of BF₃.Et₂O (0.34 g, 2.4 mmol) in anhydrous dichloromethane(8 mL) was added dropwise with stirring over 1 hour to a solution of thecrystalline (+)-CBD (3a) from Example 4 (1.1 g, 3.6 mmol) in anhydrousdichloromethane (50 mL) at −5° C. The resultant mixture was stirred for1.5 hours at −5° C. The mixture was added to a mixture of ice (100 g)and 7% NaHCO₃ (100 mL). The resultant organic phase was collected andthe aqueous phase extracted with dichloromethane (2×20 mL). The combinedorganic phases were washed with water (20 mL), dried with Na₂SO₄, andfiltered. The resultant filtrate was concentrated under reduced pressureat 40° C. The resultant residue was purified by column chromatography onsilica gel (stationary phase) using MTBE:hexane (1:100 to 3:100 (v:v))as eluent to provide crude trans-(+)-Δ⁹-THC (1b) as a yellow oil:

Yield: 0.7 g. Analysis (GC) of the crude trans-(+)-Δ⁹-THC indicated thatit had a purity of 92.6%.

5.11. Example 11 One-Pot Synthesis of Trans-(+)-Δ⁹-THC

A mixture of olivetol (14.21 g, 79.6 mmol), zinc chloride (14.25 g,102.6 mmol) and anhydrous dichloromethane (145 mL) was stirred at 40° C.for 1 hour. A solution of (−)-p-mentha-2,8-dien-1-ol (12.00 g, 76.6 mol)and anhydrous dichloromethane (45 mL) was added drop-wise over 1 hour at40° C. to the stirred olivetol-containing mixture, and the resultantmixture was stirred for an additional 40 minutes at 40° C. The mixturewas cooled to −10° C., and a solution of BF₃.Et₂O (6.7 g, 47 mmol) inanhydrous dichloromethane (12 mL) was added drop-wise over 1 hour at−10° C. The mixture was stirred for 30 minutes at −10° C. Cold water (50mL) was added, and the resultant biphasic mixture was stirred for anadditional 20 minutes at 0° C. The resultant organic phase wascollected, washed with cold water (2×50 mL), 5% aqueous sodiumbicarbonate (50 mL), and water (50 mL). The organic phase was thenconcentrated under reduced pressure at 40° C., and the resultant residue(24.8 g) was dissolved in n-heptane (140 mL) at 25° C. The resultantsolution was washed with 10% aqueous KOH (124 mL), water (2×50 mL),dried with MgSO₄ (10 g), and filtered. The resultant filtrate wasconcentrated under reduced pressure at 40° C. The resultant residue(20.7 g) was then fractionally distilled at reduced pressure (0.1 mbar)to provide trans-(+)-Δ⁹-THC (1b). Yield: 17.16 g, 69%. Analysis (GC) ofthe product indicated that it contained trans-(+)-Δ⁹-THC (1b) (49.2%),Δ⁸-iso-THC (25.31%) and dialkylolivetol (1.29%); no trans-(−)-Δ⁹-THC(1a) was detected.

5.12. Example 12 Synthesis of (±)-Δ⁹-THC

A solution of BF₃.Et₂O (0.3 g, 2.1 mmol) in anhydrous dichloromethane (8mL) was added dropwise with stirring over 1 hour to a solution of(±)-CBD (1.0 g, 3.2 mmol) in anhydrous dichloromethane (45 mL) at −5° C.The resultant mixture was stirred for 1.5 hours at −5° C. The mixturewas then added to 7% NaHCO₃ (50 mL). The resultant organic phase wascollected and the aqueous phase extracted with dichloromethane (3×30mL). The combined organic phases were washed with brine (20 mL), driedwith Na₂SO₄ and filtered. The resultant filtrate was concentrated underreduced pressure. The resultant residue was purified by columnchromatography on silica gel (stationary phase) and MTBE:hexane (1:100to 2:100 (v:v)) as eluent to provide crude (±)-Δ⁹-THC as a yellow oil.Yield: 0.6 g, 56%. Analysis (GC) of the (±)-Δ⁹-THC oil indicated that ithad a purity of 92.6% purity. The oily (±)-Δ⁹-THC (0.6 g) was dissolvedin hexane (0.5 mL), and the resultant mixture was maintained at −15° C.for 24 hours. The resultant mixture was filtered, washed with coldhexane (3×1 mL) and dried under reduced pressure to provide (±)-Δ⁹-THCas slightly rose crystals. Yield: 0.4 g. Melting point: 65-66° C.

5.13. Example 13 One-Pot Synthesis of (±)-Δ⁹-THC

A mixture of olivetol (11.84 g, 65.7 mmol), zinc chloride (11.87 g, 85.4mmol) and anhydrous dichloromethane (120 mL) was stirred at 40° C. for 1hour. A solution of (+)-p-mentha-2,8-dien-1-ol (5.00 g, 32.84 mol),(−)-p-mentha-2,8-dien-1-ol from Example 1 (5.00 g, 32.84 mol) andanhydrous dichloromethane (37 mL) was added drop-wise over 1 hour at 40°to the stirred olivetol-containing mixture, and the resultant mixturewas stirred for an additional 40 minutes at 40° C. The mixture wascooled to −10° C., and a solution of BF₃.Et₂O (5.6 g, 39.4 mmol) inanhydrous dichloromethane (10 mL) was added drop-wise over 1 hour at−10° C. The mixture was stirred for 30 minutes at −10° C., and 50 mL ofcold water were added. The resultant biphasic mixture was stirred for anadditional 20 minutes at 0° C. The resultant organic phase was collectedand washed with cold water (2×50 mL), 8% aqueous sodium bicarbonate (50mL), and water (50 mL). The organic phase was concentrated under reducedpressure at 40° C. The resultant residue (20.5 g) was dissolved inn-heptane (115 mL) at 25° C. and washed with 10% aqueous KOH (100 mL)for 40 min at 25° C. and water (50 mL). The organic phase was thenconcentrated under reduced pressure at 50° C. to provide 17.1 g of crude(±)-Δ⁹-THC as a brown oil.

A portion of the crude (±)-Δ⁹-THC oil (2.4 g) was dissolved in a minimalamount of heptane and purified by chromatography in a single pass usinga Merck-Knauer PP K-1800 preparative chromatograph with one cylinder (50mm×210 mm of LUNA CM 10 μm; loading capacities 600 mg; eluent:n-heptane). Fractions containing (±)-Δ⁹-THC were combined andconcentrated under reduced pressure at 40° C. to provide (±)-Δ⁹-THC (1).Yield: 1.1 g. Analysis (GC) of the product indicated that it contained(±)-Δ⁹-THC (1) (91.27%), iso-Δ⁸-THC (1.87%) and Δ⁸-THC (1.08%).

5.14. Example 14 Preparation of (±)-Δ⁹-THC

A mixture of olivetol (15.0 g, 83.2 mmol), zinc chloride (15.0 g, 108mmol) and anhydrous dichloromethane (150 mL) was stirred at 40° C. for 1hour. A solution of (±)-p-mentha-2,8-dien-1-ol (12.7 g, 83.2 mmol) andanhydrous dichloromethane (45 mL) was added drop-wise over 1 hour at 40°to the stirred olivetol-containing mixture, and the resultant mixturewas stirred for an additional 0.50 hours at 40° C. The mixture wascooled to −10° C., and a solution of BF₃.Et₂O (7.1 g, 49.4 mmol) inanhydrous dichloromethane (11 mL) was added drop-wise to the mixtureover 1 hour at −10° C. The mixture was stirred for 0.50 hours at −10°C., and 80 mL of cold water was added with stirring to form a biphasicmixture. The organic phase was collected and washed with cold water (80mL), 5% aqueous sodium bicarbonate (80 mL), and water (80 mL). Theorganic phase was dried over Na₂SO4 and filtered, and the resultantfiltrate was concentrated under reduced pressure to provide 28.5 g of afirst crude (±)-Δ⁹-THC residue. Analysis of the residue indicated thatit contained (±)-Δ⁹-THC (30.3%) using HPLC; and (±)-Δ⁹-THC (45.2%),Δ⁸-THC (3.2%), (±)-Δ⁸-iso-THC (17.3%). CBD (4.0%), olivetol (8.3%), anddialkylated olivetol (11.7%) using GC.

A portion of the first crude (±)-Δ⁹-THC residue (28.5 g) was dissolvedin heptane (165 mL), and the resultant solution was washed with 10% NaOH(200 mL) and water (80 mL). The organic solution was then dried byazeotropic distillation and concentrated under reduced pressure toprovide a second crude (±)-Δ⁹-THC residue. Yield: 23.5 g, 37.6%.Analysis of the second crude (±)-Δ⁹-THC residue indicated that itcontained (±)-Δ⁹-THC (37.6%) using HPLC; and (±)-Δ⁹-THC (50.7%), Δ⁸-THC(3.8%), (±)-Δ⁸-iso-THC (19.6%), CBD (4.4%), olivetol (0.0%), anddialkylated olivetol (12.8%) using GC.

5.15. Example 15 Preparation of (±)-Δ⁹-THC from a Mixture of Crude ofTrans-(−)-Δ⁹-THC and Trans-(+)-Δ⁹-THC

Trans-(−)-Δ⁹-THC was prepared as described in Example 14 for preparingthe crude second (±)-Δ⁹-THC residue, except that(+)-p-mentha-2,8-dien-1-ol was used instead of(±)-p-mentha-2,8-dien-1-ol. Analysis (HPLC) of the resultant crudetrans-(−)-Δ⁹-THC indicated that it contained 41.4% by weight oftrans-(−)-Δ⁹-THC.

Trans-(+)-Δ⁹-THC was prepared as described in Example 14 for preparingthe crude second (±)-Δ⁹-THC residue, except that(−)-p-mentha-2,8-dien-1-ol was used instead of(±)-p-mentha-2,8-dien-1-ol. Analysis (HPLC) of the resultant crudetrans-(+)-Δ⁹-THC indicated that it contained 37.5% by weight oftrans-(−)-Δ⁹-THC.

The crude trans-(−)-Δ⁹-THC (24.3 g; 10.0 g of trans-(−)-Δ⁹-THC) andtrans-(+)-Δ⁹-THC (26.7 g; 10.0 g of trans-(+)-Δ⁹-THC) were dissolved inheptane (425 mL) at 25° C. The resultant solution was admixed with 2×180mL of a solution of 9% aqueous NaOH:methanol (20:80 (v:v)). Themethanolic phases were combined and treated with 10% citric acid at 0°C. to about 5° C. until the pH was about 7. Heptane (290 mL) was added,and the resultant organic phase was washed with water. The organic phasewas then dried over Na₂SO₄ and filtered, and the resultant filtrate wasconcentrated under reduced pressure to provide 41.8 g of crude(±)-Δ⁹-THC as a brown oil. Analysis (HPLC) of the crude (±)-Δ⁹-THCindicated that it had a purity of 48%.

The crude (±)-Δ⁹-THC (41.8 g) was dissolved in heptane (85 mL), and theresultant solution was cooled to 0° C. and seeded with crystalline(±)-Δ⁹-THC (100 mg). The resultant mixture was further cooled to −15° C.for 12 hour and filtered. The resultant solids were washed with coldheptane (3×10 mL) and dried under reduced pressure to provide (±)-Δ⁹-THCas a white crystalline solid. Yield: 8.7 g, 43%. Analysis (HPLC) of theproduct indicated that it had a purity of 96.5%. The crystalline(±)-Δ⁹-THC remained white after at least three days at 25° C.

5.16. Example 16 Preparation of (±)-Δ⁹-THC from (±)-Δ⁸-THC

Preparation of (±)-9-chloro-trans-hexahydrocannabinol: A mixture ofcrude (±)-Δ⁹-THC from Example 5 (15.6 g; 9.63 g of (±)-Δ⁸-THC), zincchloride (4.66 g, 34.23 mmol) and anhydrous dichloromethane (310 mL) wasstirred for 0.5 hours at 25° C. under an Ar atmosphere. The mixture wascooled to 0° C., and gaseous hydrogen chloride was bubbled through themixture for 1.5 hours. The mixture was poured into an ice bath (150 g),and the resultant biphasic mixture was stirred for 1 hour at 0 to 5° C.The organic phase was collected and washed with cold water (2×100 mL),8% sodium bicarbonate solution (100 mL), and water (100 mL). The organicphase was dried over anhydrous Na₂SO₄ (15 g), and filtered. Theresultant filtrate was then concentrated under reduced pressure at 30°C. The resultant residue (16.3 g) was dissolved in n-heptane (33 mL),cooled to 0° C., and seeded with (±)-9-chloro-trans-hexahydrocannabinol(0.01 g). The resultant mixture was then stirred at 0° C. for 5 hours,cooled to −15° C., and stirred at −15° C. for 60 hours. The mixture wasfiltered and the resultant solids washed with cold n-heptane (14 mL).The solids were then dried under reduced pressure at 50° C. to provide(±)-9-chloro-trans-hexahydrocannabinol. Yield: 5.7 g; 32.7%. Analysis(HPLC) of the (±)-9-chloro-trans-hexahydrocannabinol indicated that ithad a purity of 95.2%. An analytical sample, recrystallized fromheptane, had a melting point of 89-90° C. The purity (HPLC) of theanalytical same was 99.6%.

Optical rotation: [α]_(D) ²⁰ 0.0° (c=0.53, CHCl₃).

¹H NMR agreed with the structure.

¹³C NMR (CDCl₃) δ 13.9, 19.1, 22.4, 24.2, 27.6, 30.4, 31.3, 31.5, 34.1,35.3, 42.0, 44.8, 48.7, 72.6, 76.7, 107.7, 108.9, 110.0, 142.8, 154.5,155.0.

The x-ray powder diffraction pattern of the crystalline (±)-9β-Cl—HHChad characteristic peaks expressed in degrees 2θ at approximately 7.5,11.2, 13.3, 14.9, 15.4, 15.9, 19.4, 19.7, 20.0 and 22.5.

Preparation of (±)-Δ⁹-THC: A mixture of potassium-tert-amylate (6.6 g),(±)-9-chloro-trans-hexahydrocannabinol (5.7 g, 16.2 mmol) and anhydroustoluene (280 mL) was stirred for 75 minutes at 65° C. The mixture wascooled to 25° C. and poured into ice water (100 g). The resultantorganic phase was collected and washed with cold water (2×100 mL), 7%sodium bicarbonate, and water (2×100 mL). The organic phase was thendried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresultant residue (5.35 g) was dissolved in n-heptane (3.4 mL), cooledto 0° C., and seeded with (±)-Δ⁹-THC (0.01 g). The resultant mixture wasstirred at 0° C. for 5 hours, cooled to −15° C., and stirred at −15° C.for 60 hours. The mixture was filtered and the resultant solids washedwith cold n-heptane (4 mL). The solids were then dried under reducedpressure at 50° C. to provide (±)-Δ⁹-THC. Yield: 3.3 g, 64.7%. Analysis(HPLC) of the product indicated that it had a purity of 97.23%.

5.17. Example 17 Purification of (±)-Δ⁹-THC

Preparation of (±)-Δ⁹-THC m-nitrobenzenesulfonate: A mixture of thesecond crude (±)-Δ⁹-THC residue of Example 14 (20.0 g; 7.52 g of(±)-Δ⁹-THC), 3-nitrobenzenesulfonyl chloride (14.5 g, 65.4 mmol),triethylamine (9.7 g) and dichloromethane (300 mL) was stirred at 25° C.for 1 hour. The resultant admixture was then treated with cold water(200 mL). The resultant organic phase was collected and washedsequentially with 10% HCl (80 mL), water (100 mL), 5% NaHCO₃ (100 mL)and water (100 mL). The organic phase was then dried over Na₂SO₄ andfiltered. The resultant filtrate was concentrated under reduced pressureto provide 25.8 g of a first crude (±)-Δ⁹-THC m-nitrobenzenesulfonateresidue. Analysis (HPLC) of the first crude (±)-Δ⁹-THCm-nitrobenzenesulfonate residue indicated that it had a purity of 42.9wt. %.

The first crude (±)-Δ⁹-THC m-nitrobenzenesulfonate residue was dissolvedin isopropanol (95 mL) at 50° C. The resultant solution was cooled toroom temperature, seeded with powdered crystalline (±)-Δ⁹-THCm-nitrobenzenesulfonate, cooled to 0° C., and stirred for 12 hour at 0°C. The resultant mixture was filtered, and the resultant solids werewashed with cold heptane (65 mL). The solids were then dried underreduced pressure to provide 10.3 g of second crude (±)-Δ⁹-THCm-nitrobenzenesulfonate residue as a yellow solid. Analysis (HPLC) ofthe second crude (±)-Δ⁹-THC m-nitrobenzenesulfonate residue indicatedthat it had a purity of 79.1%.

The second crude (±)-Δ⁹-THC m-nitrobenzenesulfonate (10.0 g) wasdissolved in dichloromethane (13 mL), and the resultant solution wasadded to a distillation pot equipped with a 10 cm Vigreux column and anaddition port. The contents of the distillation pot were then distilledwhile isopropanol (40 mL) was continuously added dropwise to the mixturethrough the addition port. The distillation was stopped when thetemperature of vapors in the head of the column reached 82.4° C. Thecontents of the distillation pot where cooled to 0° C. to 5° C., and theresultant suspension was stirred for 12 hours at 0° C. to about 5° C.The suspension was filtered, and the resultant solids were washed withcold heptane (22 mL). The solids were then dried under reduced pressureto provide crystalline (±)-Δ⁹-THC m-nitrobenzenesulfonate. Yield: 7.0 g,59%. Analysis (HPLC) of the product indicated that it had a purity of99.0%.

Melting point: 105-107° C.

X-ray powder diffraction pattern: Characteristic peaks expressed indegrees 2θ where observed at approximately 9.3, 10.6, 12.5, 15.2, 18.7,19.3, 21.2 and 22.9.

Preparation of (±)-Δ⁹-THC: A mixture of the crystalline (±)-Δ⁹-THCm-nitrobenzenesulfonate (4.5 g, 7.5 mmol), 50% NaOH (5.3 g), andmethanol (110 mL) was stirred at 50° C. for about 1-2 hours then cooledto room temperature. The cooled mixture was then treated with cold water(1×150 mL) followed by treatment with 10% HCl until the pH was about 7.The resultant mixture was extracted with heptane (3×75 mL), and thecombined organic extracts were washed with 7% NaHCO₃ (100 mL) and water(100 mL). The organic phase was dried over Na₂SO₄ and filtered. Theresultant filtrate was then concentrated under pressure to provide 2.5 gof crude (±)-Δ⁹-THC. Analysis (HPLC) of the crude product indicated thatit contained 92.6% by weight of (±)-Δ⁹-THC.

The crude (±)-Δ⁹-THC was dissolved in heptane (5 mL) at 40° C. Theresultant solution was cooled to 0° C., seeded with powdered crystalline(±)-Δ⁹-THC, and stirred for 12 hours at −15° C. The resultant mixturewas filtered and the resultant solids washed with cold heptane (3.5 mL).The solids were then dried under reduced pressure to provide (±)-Δ⁹-THCas off-white crystals. Yield: 2.1 g, 74%. The crystalline (±)-Δ⁹-THC wasstable at 25° C. in the presence of air and laboratory lighting.Analysis (HPLC) of the product indicated that it had a purity of 99.0%.An analytical sample that was recrystallized from hexane had a meltingpoint of 65°-66° C.

Optical rotation: [α]_(D) ²⁰ 0.0° (c=0.53, CHCl₃).

¹H NMR: The spectra of the product agreed with the structure.

5.18. Example 18 Preparation of (±)-Δ⁹-THC from Trans-(−)-Δ⁹-THC andTrans-(+)-Δ⁹-THC

A solution of trans-(−)-Δ⁹-THC (1a) (10 g; 9.35 g of trans-(−)-Δ⁹-THCbased on a purity of 93.5%), trans-(+)-Δ⁹-THC (1b) from Example 11 (17.0g, 8.36 g based on a purity of 49.2%) and heptane (28 mL) was cooled to0° C., seeded with (±)-Δ⁹-THC (0.02 g), and stirred for 5 hours at 0° C.The resultant mixture was cooled to −15° C. and stirred for anadditional 48 hours at −15° C. The mixture was filtered and theresultant solids washed with cold n-heptane (4 mL). The solids were thendried under reduced pressure at 35° C. to provide crude (±)-Δ⁹-THC.Yield: 11.4 g, 68%. Analysis (HPLC) of the crude (±)-Δ⁹-THC indicatedthat it had a purity of 93.6%.

The crude (±)-Δ⁹-THC (11.2 g) was dissolved in heptane (15 g) at 50° C.,and the mixture was cooled with stirring to 0° C. The resultant mixturewas stirred at 0° C. for 2 hours, cooled to −15° C., and stirred for anadditional 48 hours at −15° C. The mixture was filtered and theresultant crystalline solids washed with cold n-heptane (4 mL). Thesolids were then dried under reduced pressure at 35° C. to providecrystalline (±)-Δ⁹-THC. Yield: 9.2 g, 82%. Analysis (HPLC) of thecrystalline (±)-Δ⁹-THC indicated that it had a purity of 97.7%.

5.19. Example 19 Preparation of Crystalline (±)-Δ⁹-THC

(+)-Δ⁹-THC (2.70 g, 2.55 g of trans-(+)-Δ⁹-THC based on a purity of94.3%) (obtained from enantioselective chromatography of crystalline(±)-Δ⁹-THC) as described in Example 21) and trans-(−)-Δ⁹-THC fromExample 9 (3.36 g, 2.76 g of trans-(−)-Δ⁹-THC based on purity of 82.2%)were dissolved in heptane (9.5 mL). The resultant solution was cooled to0° C. and seeded with crystalline (±)-Δ⁹-THC (0.01 g). The resultantadmixture was stirred for 5 hours at 0° C. and for 72 hour at −15° C.The resultant mixture was filtered and the resultant solids washed withcold heptane (8 mL). The solids were then dried under reduced pressureat 35° C. to provide crystalline (±)-Δ⁹-THC. Yield: 4.4 g, 79.7%.Analysis (HPLC) of the product indicated that it had a purity of 98.7%.

5.20. Example 20 Preparation of Crystalline (±)-Δ⁹-THC

Crude trans(−)-Δ⁹-THC and crude trans-(+)-Δ⁹-THC were prepared byprocesses as described in Examples 9 and 11, respectively. Crudetrans-(−)-Δ⁹-THC (27.7 g; containing 10.0 g of trans-(−)-Δ⁹-THC) in 65mL of heptane and crude trans-(+)-Δ⁹-THC (24.3 g; containing 10.0 g oftrans-(+)-Δ⁹-THC), 50% and heptane (315 mL) was admixed with amethanolic caustic solution containing 50% caustic (33 g), water (16.5mL) and methanol (190 mL) for 20 minutes at 25° C. The resultant purplemethanolic caustic (lower) phase was collected, and the organic phasewas admixed again with a methanolic caustic solution containing 50%caustic (33 g), water (16.5 mL) and methanol (190 mL) for 20 minutes at25° C. The resultant methanolic caustic phase was collected, and thecombined methanolic caustic phases were treated slowly with a 10%solution of citric acid in water (545 g). The resultant yellow admixturewas then extracted with heptane (200 g). The resultant organic phasecollected and washed with water (150 mL), dried over Na₂SO₄, andfiltered. The resultant filtrate was dried by azeotropic distillationand concentrated under reduced pressure. The resultant red oil (41.76 g)was dissolved in heptane (57 g), cooled to 0° C., and seeded with 100 mgof crystalline (±)-Δ⁹-THC. The resultant admixture was cooled to −15° C.and stirred at −15° C. for 12 hours. The resultant mixture wassuction-filtered, and the solids were washed with cold heptane (3×10mL). The resultant yellow solids were allowed to dry under suction toprovide 12.45 g of crude (±)-Δ⁹-THC.

The crude (±)-Δ⁹-THC (12.45 g) was dissolved in heptane (25 mL) at 50°C., and the resultant solution was cooled to −10° C. for 2-3 hours. Theresultant mixture was suction-filtered and the solids washed 3 timeswith cold heptane (10, 10, and 20 mL). The solids were then allowed todry under suction to provide (±)-Δ⁹-THC as white crystals. Yield: 8.70g; 14% yield (based on olivetol); 44% yield based on (−)-Δ⁹-THC and(+)-Δ⁹-THC. Analysis (HPLC) of the crystalline (±)-Δ⁹-THC indicated thatit had a purity of 96.45%.

5.21. Example 21 Resolution of Trans-(−)-Δ⁹-THC and Trans-(+)-Δ⁹-THCfrom (±)-Δ⁹-THC

(±)-Δ⁹-THC (2.00 g, 97.7% pure) was eluted by flash chromatography on aMerck column (210×50 mm) using Chiralpak® AD™ 20 μm chiral (Daicel,Tokyo, Japan) as the stationary phase Goading capacity 500 mg perinjection, UV at 228 nm) and n-heptane:2-propanol (95:5 (v:v)) as themobile phase at a flow rate of 200 mL/min at 20° to 25° C. The fractionsin which only trans-(−)-Δ⁹-THC was observed were combined, and thevolatiles removed using a rotary evaporator at 35° to 40° C. to providetrans-(−)-Δ⁹-THC (1a). Yield: 0.89 g; 89%. Analysis of the product(HPLC) indicated that it was at least 99.9% pure, i.e., no othercannabinoids were detected.

5.22. Example 22 Resolution of Trans-(−)-Δ⁹-THC and Trans-(+)-Δ⁹-THCfrom (±)-Δ⁹-THC

Crystalline (±)-Δ⁹-THC from Example 15 (3.8 g) was dissolved in 8 ml ofheptane:2-propanol (95:5 (v:v)) mixture. The resultant solution wasinjected into a 2 inch stainless steel “Load and Lock” column (Varian)packed with Chiralpak® AD chiral derivatized silica (ChiralTechnologies, Inc. Exton, Pa.).

Elution was carried out under isocratic conditions with a solution ofheptane:isopropanol (95:5 (v:v)) at a temperature of about 25° C. and ata flow rate of 250 mL of eluent/min. Detection of compounds in theeluent was carried out by UV absorption at 235 nm.

Trans-(+)-Δ⁹-THC eluted first, and the combined trans-(+)-Δ⁹-THC eluentswere concentrated under reduced pressure to provide 1.5 g oftrans-(+)-Δ⁹-THC (1b) as a reddish-yellow oil.

Trans-(−)-Δ⁹-THC eluted after the trans-(+)-Δ⁹-THC, and the combinedtrans-(−)-Δ⁹-THC eluents were concentrated under reduced pressure toprovide trans-(−)-Δ⁹-THC (1a) as a thick viscous reddish-yellow oil.Yield: 1.4 g. Analysis (HPLC) of the trans-(−)-Δ⁹-THC product indicatedthat it had a purity of 99.4%.

5.23. Example 23 Resolution of Trans-(−)-Δ⁹-THC and Trans-(+)-Δ⁹-THCfrom (±)-Δ⁹-THC

Crystalline (±)-Δ⁹-THC from Example 13 (about 2.0 g) was dissolved in aabout 26 ml of 95:5 heptane:IPA (v:v) mixture to provide a 10 wt. %solution. A portion of the 10% solution (about 5 g) was injected into220×50 mm stainless steel column (Merck) packed with Chiralpak® AD 20 μmchiral derivatized silica (Daicel, Tokyo, Japan). Elution was carriedout under isocratic conditions with a solution of heptane:2-propanol(95:5 (v:v)) solvent at about 25° C. and at a flow rate of 200 mL ofeluent/min. Detection of products in the eluent was carried out by UVabsorption at 228 nm. The elution of the remaining portions of the 10%solution was carried on about 3×5 g samples as described above.

The fractions containing (+)-Δ⁹-THC were combined and concentrated underreduced pressure to provide (+)-Δ⁹-THC as reddish-yellow oil.

Yield: 1.0 g. Analysis (HPLC) of the oil indicated that it had a purityof 97.0%.

The fractions containing trans-(−)-Δ⁹-THC were combined and concentratedunder reduced pressure to provide trans-(−)-Δ⁹-THC (1a) as a thickviscous reddish-yellow oil. Yield: 1.0 g. Analysis (HPLC) of the productindicated that it had a purity of 99.9%.

The product was stored in a freezer and protected from light and oxygen.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

1-24. (canceled)
 25. A trans-(−)-Δ⁹-tetrahydrocannabinol compositioncomprising at least 99.0% by weight of trans-(−)-Δ⁹-tetrahydrocannabinoland less than 0.05% of Δ⁹-tetrahydrocannabinol acid based on the totalamount of cannabinoids.
 26. The trans-(−)-Δ⁹-tetrahydrocannabinolcomposition of claim 1 comprising at least 99.5% by weight oftrans-(−)-Δ⁹-tetrahydrocannabinol based on the total amount ofcannabinoids.
 27. The trans-(−)-Δ⁹-tetrahydrocannabinol composition ofclaim 2 comprising at least 99.9% by weight oftrans-(−)-Δ⁹-tetrahydrocannabinol based on the total amount ofcannabinoids.
 28. The trans-(−)-Δ⁹-tetrahydrocannabinol composition ofclaim 1, wherein the composition comprises up to about 99.95% by weightof trans-(−)-Δ⁹-tetrahydrocannabinol based on the total amount ofcannabinoids.
 29. The trans-(−)-Δ⁹-tetrahydrocannabinol composition ofclaim 1, wherein the composition comprises up to about 99.98% by weightof trans-(−)-Δ⁹-tetrahydrocannabinol based on the total amount ofcannabinoids.
 30. A method for preparing atrans-(−)-Δ⁹-tetrahydrocannabinol composition, comprising: allowing acomposition comprising (±)-Δ⁹-tetrahydrocannabinol to separate on achiral stationary phase in the presence of an eluting solvent to providea trans-(−)-Δ⁹-tetrahydrocannabinol composition comprising at leastabout 98% by weight of trans-(−)-Δ⁹-tetrahydrocannabinol based on thetotal amount of trans-(−)-Δ⁹-tetrahydrocannabinol andtrans-(+)-Δ⁹-tetrahydrocannabinol; wherein the(±)-Δ⁹-tetrahydrocannabinol was obtained by allowingtrans-(−)-Δ⁹-tetrahydrocannabinol and trans-(+)-Δ⁹-tetrahydrocannabinolto crystallize from a first composition comprisingtrans-(−)-Δ⁹-tetrahydrocannabinol, trans-(+)-Δ⁹-tetrahydrocannabinol,and a non-polar organic solvent to provide crystalline(±)-Δ⁹-tetrahydrocannabinol and a liquid phase.
 31. The method of claim30, wherein the trans-(−)-Δ⁹-tetrahydrocannabinol composition comprisesat least about 99.5% by weight of trans-(−)-Δ⁹-tetrahydrocannabinolbased on the total amount of trans-(−)-Δ⁹-tetrahydrocannabinol andtrans-(+)-Δ⁹-tetrahydrocannabinol.
 32. The method of claim 31, whereinthe trans-(−)-Δ⁹-tetrahydrocannabinol composition comprises at leastabout 99.8% by weight of trans-(−)-Δ⁹-tetrahydrocannabinol based on thetotal amount of trans-(−)-Δ⁹-tetrahydrocannabinol andtrans-(+)-Δ⁹-tetrahydrocannabinol.
 33. The method of claim 30, whereinthe trans-(−)-Δ⁹-tetrahydrocannabinol composition comprises at leastabout 98% by weight of trans-(−)-Δ⁹-tetrahydrocannabinol based on thetotal amount of cannabinoids.
 34. The method of claim 33, wherein thetrans-(−)-Δ⁹-tetrahydrocannabinol composition comprises at least about99% by weight of trans-(−)-Δ⁹-tetrahydrocannabinol based on the totalamount of cannabinoids.
 35. The method of claim 34, wherein thetrans-(−)-Δ⁹-tetrahydrocannabinol composition comprises at least about99.5% by weight of trans-(−)-Δ⁹-tetrahydrocannabinol based on the totalamount of cannabinoids.
 36. The method of claim 30, wherein thetrans-(−)-Δ⁹-tetrahydrocannabinol is present in the first composition inan amount from about 0.75 to about 1.25 molar equivalents per molarequivalent of trans-(+)-Δ⁹-tetrahydrocannabinol.
 37. The method of claim36, wherein the trans-(−)-Δ⁹-tetrahydrocannabinol is present in thefirst composition in an amount from about 0.9 to about 1.1 molarequivalents per molar equivalent of trans-(+)-Δ⁹-tetrahydrocannabinol.38. The method of claim 37, wherein thetrans-(−)-Δ⁹-tetrahydrocannabinol is present in the first composition inan amount from about 0.95 to about 1.05 molar equivalents per molarequivalent of trans-(+)-Δ⁹-tetrahydrocannabinol.
 39. The method of claim36, wherein the trans-(−)-Δ⁹-tetrahydrocannabinol is present in thefirst composition in an amount of about 1 molar equivalent per molarequivalent of trans-(+)-Δ⁹-tetrahydrocannabinol.
 40. The method of claim30, wherein the (±)-Δ⁹-tetrahydrocannabinol comprises at least about 95%by weight of trans-(−)-Δ⁹-tetrahydrocannabinol andtrans-(+)-Δ⁹-tetrahydrocannabinol based on the total amount ofcannabinoids.
 41. The method of claim 40, wherein the(±)-Δ⁹-tetrahydrocannabinol comprises at least about 98% by weight oftrans-(−)-Δ⁹-tetrahydrocannabinol and trans-(+)-Δ⁹-tetrahydrocannabinolbased on the total amount of cannabinoids.
 42. The method of claim 41,wherein the (±)-Δ⁹-tetrahydrocannabinol comprises at least about 99% byweight of trans-(−)-Δ⁹-tetrahydrocannabinol andtrans-(+)-Δ⁹-tetrahydrocannabinol based on the total amount ofcannabinoids.
 43. The method of claim 30, wherein the non-polar organicsolvent is a straight-chain or branch-chain (C₄-C₁₀)aliphatichydrocarbon, a (C₄-C₁₀)cycloaliphatic hydrocarbon, or any mixturethereof.
 44. The method of claim 43, wherein the straight-chain orbranch-chain hydrocarbon is pentane, hexane, heptane, isooctane, or anymixture thereof.
 45. The method of claim 44, wherein the straight-chainor branch-chain hydrocarbon is n-heptane.
 46. The method of claim 30,wherein the first composition further comprises a(±)-Δ⁹-tetrahydrocannabinol seed crystal.
 47. The method of claim 30,wherein the eluting solvent is a straight-chain or branch-chain(C₁-C₄)alkyl substituted with one or more —OH, —OR₁, —OC(O)R₁, —C(O)OR₁,-halo, or —CN; a straight-chain or branch-chain (C₄-C₁₀)aliphatichydrocarbon; a (C₅-C₇)cycloaliphatic hydrocarbon optionally substitutedwith one or more —R₁; a (C₄-C₇)cyclic ether optionally substituted withone or more —R₁; an aromatic hydrocarbon optionally substituted with oneor more —R₁, -halo, —CH₂(halo), —CH(halo)₂, —C(halo)₃-O(C₁-C₆)alkyl; orany mixture thereof, where R₁ is (C₁-C₄)alkyl.
 48. The method of claim47, wherein the eluting solvent is a straight-chain or branch-chain(C₁-C₄)alkyl substituted with one or more —OH, —OR₁, —OC(O)R₁, —C(O)OR₁,-halo, or —CN.
 49. The method of claim 48, wherein the eluting solventis methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,tert-butanol, methylene chloride, or any mixture thereof.
 50. The methodof claim 49, wherein the eluting solvent is a mixture of n-heptane and2-propanol.
 51. The method of claim 30, wherein the chiral stationaryphase is an inorganic oxide having a pendant group bonded to theinorganic oxide.
 52. The method of claim 51, wherein the inorganic oxideis silica or alumina.
 53. The method of claim 52, wherein the inorganicoxide is silica.
 54. The method of claim 53, wherein the pendant groupis amylose tris(3,5-dimethylphenylcarbamate).
 55. Atrans-(+)-Δ⁹-tetrahydrocannabinol composition comprising at least about98% by weight of trans-(+)-Δ⁹-tetrahydrocannabinol based on the totalamount of cannabinoids.
 56. A method for preparing atrans-(+)-Δ⁹-tetrahydrocannabinol composition, comprising: allowing acomposition comprising (±)-Δ⁹-tetrahydrocannabinol to separate on achiral stationary phase to provide a trans-(+)-Δ⁹-tetrahydrocannabinolcomposition comprising at least about 98% by weight oftrans-(+)-Δ⁹-tetrahydrocannabinol based on the total amount oftrans-(+)-Δ⁹-tetrahydrocannabinol and trans-(−)-Δ⁹-tetrahydrocannabinol;wherein the (±)-Δ⁹-tetrahydrocannabinol was obtained by allowingtrans-(−)-Δ⁹-tetrahydrocannabinol and trans-(+)-Δ⁹-tetrahydrocannabinolto crystallize from a first composition comprisingtrans-(−)-Δ⁹-tetrahydrocannabinol, trans-(+)-Δ⁹-tetrahydrocannabinol,and a non-polar organic solvent to provide crystalline(±)-Δ⁹-tetrahydrocannabinol and a liquid phase.
 57. A method forpreparing a composition comprising trans-(−)-Δ⁹-tetrahydrocannabinol,comprising: allowing a composition comprising(±)-Δ⁹-tetrahydrocannabinol and an eluting solvent to separate on achiral stationary phase to provide a trans-(−)-Δ⁹-tetrahydrocannabinolcomposition, wherein the (±)-Δ⁹-tetrahydrocannabinol is obtained fromcrystalline (±)-Δ⁹-tetrahydrocannabinol.
 58. A method for preparing acomposition comprising trans-(+)-Δ⁹-tetrahydrocannabinol, comprising:allowing a composition comprising (±)-Δ⁹-tetrahydrocannabinol and aneluting solvent to separate on a chiral stationary phase to provide atrans-(+)-Δ⁹-tetrahydrocannabinol composition, wherein the(±)-Δ⁹-tetrahydrocannabinol is obtained from crystalline(±)-Δ⁹-tetrahydrocannabinol.
 59. A method for treating pain, comprisingadministering to a patient in need thereof an effective amount of thetrans-(−)-Δ⁹-tetrahydrocannabinol composition of claim 25, 26, 27, or28.
 60. A method for treating emesis, comprising administering to apatient in need thereof an effective amount of thetrans-(−)-Δ⁹-tetrahydrocannabinol composition of claim 25, 26, 27, or28.
 61. A method for treating loss of appetite, comprising administeringto a patient in need thereof an effective amount of thetrans-(−)-Δ⁹-tetrahydrocannabinol composition of claim 25, 26, 27, or28.
 62. A method for treating weight loss, comprising administering to apatient in need thereof an effective amount of thetrans-(−)-Δ⁹-tetrahydrocannabinol composition of claim 25, 26, 27, or28.
 63. A dosage form comprising an effective amount of thetrans-(−)-Δ⁹-tetrahydrocannabinol composition of claim 25, 26, 27, or 28and a pharmaceutically acceptable carrier.
 64. An encapsulated dosageform comprising an effective amount of thetrans-(−)-Δ⁹-tetrahydrocannabinol composition of claim 25, 26, 27, or 28and a pharmaceutically acceptable carrier.
 65. The encapsulatedpharmaceutical dosage form of claim 64, wherein the pharmaceuticallyacceptable carrier is sesame oil.
 66. The encapsulated pharmaceuticaldosage form of claim 65, wherein the amount oftrans-(−)-Δ⁹-tetrahydrocannabinol is from about 0.1 mg to about 20 mg.67. The encapsulated pharmaceutical dosage form of claim 66, wherein theamount of trans-(−)-Δ⁹-tetrahydrocannabinol is about 2.5 mg.
 68. Theencapsulated pharmaceutical dosage form of claim 66, wherein the amountof trans-(−)-Δ⁹-tetrahydrocannabinol is about 5 mg.
 69. The encapsulatedpharmaceutical dosage form of claim 66, wherein the amount oftrans-(−)-Δ⁹-tetrahydrocannabinol is about 10 mg.
 70. A method formaking crystalline (±)-Δ⁹-tetrahydrocannabinol comprising: allowingtrans-(−)-Δ⁹-tetrahydrocannabinol and trans-(+)-Δ⁹-tetrahydrocannabinolto crystallize from a first composition comprisingtrans-(−)-Δ⁹-tetrahydrocannabinol, trans-(+)-Δ⁹-tetrahydrocannabinol,and a non-polar organic solvent to provide crystalline(±)-Δ⁹-tetrahydrocannabinol, wherein the first composition was obtainedby: (a) forming a biphasic composition comprising (i) a first organicphase, and (ii) an alcoholic-caustic phase containing thetrans-(−)-Δ⁹-tetrahydrocannabinol and thetrans-(+)-Δ⁹-tetrahydrocannabinol; (b) separating thetrans-(−)-Δ⁹-tetrahydrocannabinol and thetrans-(+)-Δ⁹-tetrahydrocannabinol from the alcoholic-caustic phase; and(c) forming a first composition comprising thetrans-(−)-Δ⁹-tetrahydrocannabinol from step (b),trans-(+)-Δ⁹-tetrahydrocannabinol, and a non-polar organic solvent. 71.A method for making crystalline (±)-Δ⁹-tetrahydrocannabinol comprising:allowing trans-(−)-Δ⁹-tetrahydrocannabinol andtrans-(+)-Δ⁹-tetrahydrocannabinol to crystallize from a firstcomposition comprising trans-(−)-Δ⁹-tetrahydrocannabinol,trans-(+)-Δ⁹-tetrahydrocannabinol, and a non-polar organic solvent toprovide crystalline (±)-Δ⁹-tetrahydrocannabinol, wherein the firstcomposition was obtained by: (a) forming a biphasic compositioncomprising (i) a first organic phase, and (ii) an alcoholic-causticphase containing trans-(−)-Δ⁹-tetrahydrocannabinol; (b) separating thetrans-(−)-Δ⁹-tetrahydrocannabinol from the alcoholic-caustic phase; and(c) contacting the trans-(−)-Δ⁹-tetrahydrocannabinol from step (b) withtrans-(+)-Δ⁹-tetrahydrocannabinol and a non-polar organic solvent toform the first composition.
 72. A method for making crystalline(±)-Δ⁹-tetrahydrocannabinol comprising: allowingtrans-(−)-Δ⁹-tetrahydrocannabinol and trans-(+)-Δ⁹-tetrahydrocannabinolto crystallize from a first composition comprisingtrans-(−)-Δ⁹-tetrahydrocannabinol, trans-(+)-Δ⁹-tetrahydrocannabinol,and a non-polar organic solvent to provide crystalline(±)-Δ⁹-tetrahydrocannabinol, wherein the first composition was obtainedby: (a) forming a biphasic composition comprising (i) a first organicphase, and (ii) an alcoholic-caustic phase containingtrans-(+)-Δ⁹-tetrahydrocannabinol; (b) separating thetrans-(+)-Δ⁹-tetrahydrocannabinol from the alcoholic-caustic phase; and(c) contacting the trans-(+)-Δ⁹-tetrahydrocannabinol from step (b) withtrans-(−)-Δ⁹-tetrahydrocannabinol and a non-polar organic solvent toform the first composition.